WO2005032559A1 - Nitric oxide donating derivatives for the treatment of cardiovascular disorders - Google Patents
Nitric oxide donating derivatives for the treatment of cardiovascular disorders Download PDFInfo
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- WO2005032559A1 WO2005032559A1 PCT/CA2004/001805 CA2004001805W WO2005032559A1 WO 2005032559 A1 WO2005032559 A1 WO 2005032559A1 CA 2004001805 W CA2004001805 W CA 2004001805W WO 2005032559 A1 WO2005032559 A1 WO 2005032559A1
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- C07C211/52—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
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- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/56—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/64—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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- C07C245/02—Azo compounds, i.e. compounds having the free valencies of —N=N— groups attached to different atoms, e.g. diazohydroxides
- C07C245/06—Azo compounds, i.e. compounds having the free valencies of —N=N— groups attached to different atoms, e.g. diazohydroxides with nitrogen atoms of azo groups bound to carbon atoms of six-membered aromatic rings
- C07C245/08—Azo compounds, i.e. compounds having the free valencies of —N=N— groups attached to different atoms, e.g. diazohydroxides with nitrogen atoms of azo groups bound to carbon atoms of six-membered aromatic rings with the two nitrogen atoms of azo groups bound to carbon atoms of six-membered aromatic rings, e.g. azobenzene
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- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
- C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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- C07C317/22—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
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- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/32—2,3-Dihydro derivatives, e.g. flavanones
Definitions
- the present invention relates to the field of synthesis and administration of flavonoids and derivatives thereof suitable for incorporation into foods, pharmaceuticals, nutraceuticals and the methods of treating individuals in need with the same.
- Cardiovascular disease is a general term used to identify a group of disorders of the heart and blood vessels including hypertension, coronary heart disease, cerebrovascular disease, peripheral vascular disease, heart failure, rheumatic heart disease, congenital heart disease and cardiomyopathies.
- the leading cause of cardiovascular disease is atherosclerosis, the build up of lipid deposits on arterial walls. Elevated levels of cholesterol in the blood are highly correlated to the risk of developing atherosclerosis, and thus significant medical research has been devoted to the development of therapies that decrease blood cholesterol.
- Atherosclerosis is associated with endothelial dysfunction, a disorder wherein normal function of the vasculature lining is impaired, which contributes to the pathogenesis of atherosclerosis, in addition to being a prominent risk factor for numerous other cardiovascular disorders such as angina, myocardial infarction and cerebrovascular disease.
- Hallmarks of endothelial dysfunction include increased oxidative vascular stress and vasoconstriction, as well as elevated levels of cholesterol in the blood, which all promote one another to accelerate the development of cardiovascular disease. In order to most successfully disrupt the development of disease, improved therapeutic strategies against the multiple causal risk factors of cardiovascular disease are needed.
- LDL Low density lipoproteins
- EDL intermediate density lipoproteins
- VLDL very low density lipoproteins
- CURRENT TREATMENTS FOR HYPERLEP EDEMLAS Currently approved cholesterol lowering drugs provide therapeutic benefit by attacking the normal cholesterol metabolic pathways at a number of different points. Bile acid binding resins, such as cholestyramine, adsorb to bile acids and are excreted out of the body, resulting in an increased conversion of cholesterol to bile acids, consequently lowering blood cholesterol. Resins only lower serum cholesterol a maximum of 20%, cause gastrointestinal side effects and can not be given concomitantly with other medications as the resins will bind to and cause the excretion of such other drugs.
- Bile acid binding resins such as cholestyramine
- Niacin inhibits lipoprotein synthesis and decreases production of VLDL particles, which are needed to make LDL.
- Fibrates such as clofibrate and fenofibrate, are believed to activate transcription factors belonging to the peroxisome proliferator-activated receptor (PPAR) family of nuclear hormone receptors. These transcription factors up-regulate genes involved in the production of HDL and down-regulate genes involved in the production of LDL. Fibrates are used to treat hyperlipidemias because they reduce serum triglycerides by lowering the VLDL fraction.
- PPAR peroxisome proliferator-activated receptor
- Statins also known as HMG CoA reductase inhibitors, decrease VLDL, LDL and IDL cholesterol by blocking the rate-limiting enzyme in hepatic cholesterol synthesis. Statins increase HDL levels only marginally, and numerous liver and kidney dysfunction side effects have been associated with the use of these drugs.
- Ezetimibe is the first approved drug in a new class of cardiovascular therapeutics, which functions by inhibiting cholesterol uptake in the intestine. Ezetimibe lowers LDL but does not appreciably increase HDL levels, and does not address the cholesterol which is synthesized in the body nor the cholesterol circulating in the bloodstream or present in atherosclerotic plaques. Other compounds that have also been discovered to affect cholesterol absorption include the bile-acid binding agent cholestyramine and the phytosterols.
- NO is well known to inhibit platelet aggregation, a necessary step in the development of the lipid plaques that characterize atherosclerosis.
- NO is an important endogenous mediator that inhibits leukocyte adhesion, which is a major step in the development of atherosclerosis and is probably the result of increased vascular oxidative stress in hyperlipidemic patients.
- Adherent leukocytes further increase oxidant stress by releasing large amounts of reactive oxygen species.
- Increased vascular oxidative stress and hypercholesterolemia have individually been identified as contributors to the cause of reduced NO bioavailability. Increased oxidation also leads to free-radical mediated lipid peroxidation, another inducer of atherosclerotic lesion formation. In summary, it would appear that a positive feedback loop exists wherein each of these three major factors, hypercholesterolemia, vascular oxidative stress and reduced bioavailability of NO, increases the extent and pathological severity of the other factors.
- NITRIC OXEDE AS A THERAPY FOR ATHEROSCLEROSIS - ENDOTHELIAL DYSFUNCTION
- Therapeutic modalities that employ compounds known to donate NO have been employed clinically in an attempt to break the atherosclerosis - endothelial dysfunction cycle without success.
- Exogenous NO released by NO-donating drugs has been demonstrated to generate not only NO but also peroxynitrite anion, a potent oxidant, which further increases oxidative stress.
- the generation of peroxynitrite by NO-donors and subsequent down regulation of responsiveness to NO caused by increased oxidative stress may underlie the well documented tolerance that develops in patients treated chronically with organic nitrate esters.
- NO-donating drugs are also believed to require a transition through a thiol intermediate prior to their liberation of NO, and the bioavailability of thiols is significantly diminished in such conditions of oxidative stress.
- anti-oxidants have been provided to patients in combination with NO-donors. Some studies have demonstrated that combination of anti-oxidants with NO-donors significantly increased endothelial-dependent vasodilation in hypercholesteremic subjects.
- NO-donating and anti-oxidant agents with existing therapies that treat the hypercholesterolemia underlying atherosclerosis is also a suboptimal approach, as the currently approved drugs do not effectively exploit the use of increasing HDL to efficiently transport cholesterol out of the body.
- a preferred anti-oxidant and/or NO- donor combination would ensure that the anti-oxidant and NO-donor were present in the same location and same time in the body, in order for the anti-oxidant to most effectively counteract the potential oxidative side effects of NO.
- the difficulty in meeting this need using a combination of several different drugs with differing release rates and bioavailability is likely to be exacerbated by the short half life of NO in the cellular environment once released from the donor molecule.
- ROS Reactive oxygen species
- One of the most effective methods to counter ROS is to "mop" up the reactive groups by providing an anti-oxidant compound which binds to the ROS and thus prevents them from inappropriately bonding to key proteins and DNA in the cell.
- Very effective anti- oxidant compounds capable of eliminating ROS often contain at least one phenolic ring structure.
- a phenol ring is a reactive species with which a ROS may form a covalent bond, which thereby abolishes the strong oxidative reactivity of the ROS.
- Stilbenes, polyphenols and flavonoids all contain at least two phenolic ring structures, thereby making them potentially effective as anti-oxidant agents.
- the French Paradox has been correlated to the high quantities of red wine consumed by the French population compared to that consumed by the North American population.
- Resveratrol is highly abundant in the skin of red grapes and thus is found in significant quantities in red wine but is almost completely absent in white wine or other alcoholic beverages.
- the mechanism by which resveratrol reduces the incidence of cardiovascular disease remains a topic of considerable debate, with several competing hypotheses.
- Resveratrol has been demonstrated to be a potent anti-oxidant, which is suggested to result in lower levels of peroxidation of LDL particles, and subsequently to inhibit atherogenesis.
- Resveratrol has also been implicated as an inhibitor of leukocyte adhesion and platelet aggregation.
- resveratrol is being investigated as a potential anti-cancer therapeutic due to its described capability of modulating the activity levels of p21 and p53.
- Resveratrol has been identified as an anti-inflammatory agent, with proposed mechanisms including the inhibition of the cyclooxygenase-1 enzyme (See US Patent 6,541,045; Jayatilake et al. I Nat Prod. 1993 Oct; 56(10):1805-10; US Patent 6,414,037) and protein kinase inhibition (US Patent Application 0030171429). Consequently, resveratrol may have the potential to be employed therapeutically to treat arthritic disorders, asthmatic disorders, psoriatic disorders, gastrointestinal disorders, ophthalmic disorders, pulmonary inflammatory disorders, cancer, as an analgesic, as an anti-pyretic, or for the treatment of inflammation that is associated with vascular diseases, central nervous system disorders and bacterial, fungal and viral infections.
- Resveratrol was recently described as a sirtuin-activating compound, and was suggested to increase longevity through a direct interaction with SirTl, leading to down-regulation of p53. Resveratrol is also known to antagonize the aryl hydrocarbon receptor and agonize the estrogen receptor, and has been described to mediate activity through activation of the ERK 1/2 pathway and through increasing the activity of the transcription factor egr- 1. More recently, we have shown that resveratrol has the ability to increase the transcription of apolipoprotein Al, putatively mediated through Site S, a nucleotide sequence in the promoter region of the ApoA-1 gene (PCT/CA03/01220). A sequence, AGCCCCCGC, found within Site S, has been described as an
- Egr-1 response element consensus sequence. This motif is contained within the nucleotides spanning -196 to -174 of the human APO Al promoter (Kilbourne et al. 1995, JBC, 270(12):7004-10). Without being bound by any particular theory, this AGCCCCCGC element found to be contained within Site S is a sequence through which resveratrol is proposed to mediate its activity, but this is not to the exclusion of other potentially required elements.
- nucleotide sequence comprising Site S or about any 8 contiguous bases of the AGCCCCCGC element act as an enhancer element when operably linked to a heterologous promoter in order to modulate the expression of a reporter gene.
- resveratrol may be better or safer in the absence of alcohol.
- Many stilbenes, polyphenols and flavonoids with potential beneficial qualities may be created that are not naturally synthesized and have not yet been described or made available for testing. Such compounds must be created in the laboratory and tested in appropriate in vitro and in vivo assays to demonstrate beneficial therapeutic activities before being examined in human clinical studies.
- naringenin as one example flavonoid of many components found in administered citrus juice
- naringenin as one example flavonoid of many components found in administered citrus juice
- flavonoids such as naringenin, or stilbenes such as resveratrol, or other polyphenols to use for human therapy in the treatment of cardiovascular disorders.
- IMPROVED THERAPEUTIC OUTCOME Compounds administered as therapeutic agents to individuals in need are typically metabolized in the body to a variety of metabolites prior to excretion. Such metabolites often differ from the parent compound in terms of toxicity, efficacy and length of residence in the serum. For many compounds, the metabolites are not as effective as the parent compound and can be more toxic. In the metabolism of exogenously administered therapeutic compounds, a number of different modifications may occur, for example the addition of various chemical moieties or removal of key groups. One metabolic reaction that occurs in vivo is the removal of hydroxyl groups.
- hydroxyl groups from compounds with a core structure of flavonoids, stilbenes, and other polyphenolic compounds, the nitric oxide donating derivatives of which comprise compounds of the invention may significantly reduce the ability of the compounds to positively affect cholesterol metabolism, as the aforementioned hydroxyl groups are an integral part of the active site of such molecules. It therefore advantageously improves the beneficial effect of administration of compounds of the invention if some mechanism is utilized for the protection of the hydroxyl groups to reduce the rate of metabolism and thus increase the time for which the compounds remain in the body.
- One protection mechanism commonly employed in laboratory chemical reactions is the use of protecting groups, which are attached to an easily modified, labile chemical group of a larger molecule, in order to prevent the modification or loss of the labile group.
- Protecting groups may be later removed to restore the original molecule, with no changes to any of the covalent bonds in the entire molecule.
- a similar form of protection may be used for compounds intended to be admimstered to a patient, where known reactions in the body are likely to occur that will reconstitute the active molecule.
- the speed at which protecting groups are released from a molecule may be controlled to affect the rate at which the drug is released. It is an object of the present invention to provide efficacious compounds of extended half-life in the body and/or postponing excretion.
- a stilbene compound comprising the following structure:
- Rl, R2, R3, R4, R5, R6, R7, R8, R9 and R10 may each be independently hydrogen, hydroxyl [OH], hydroxyalkyl, aminoalkyl, Bromide (Br), Iodide (I), nitrooxy [ONO.sub.2], methoxy [OCH.sub.3], ethoxy [OCH.sub2CH.sub.3], fluoride [F], chloride [Cl], CF.sub.3, CCl.sub.3, phosphate, Rll, R12, OR11, OR12, OCOR11, OCOR12, O-sulfate [the sulfate conjugate], or O-glucoronidate [the glucoronic (AKA glucuronic) acid conjugates], with the proviso that at least one of R1-R10 is nitrooxy, R12, OR12, or OCOR12; and wherein OCOR means and R is Rll or R12 wherein Rll is C ⁇ . ⁇ $ ,
- R12 is CM S , aryl, heteroaryl or a derivative thereof, wherein said derivative is optionally substituted, optionally branched, may have one or more of the C atoms replaced by S, N or O, and containing one or more ONO.sub.2 and wherein X can be a single, double or triple bond.
- a flavonoid compound comprising the following structure:
- Rl, R2, R3, R4, R5, R6, R7, R8, R9, RIO, R13 and R14 may each be independently hydrogen, hydroxyl [OH], hydroxyalkyl, aminoalkyl, Bromide (Br), Iodide (I), nitrooxy [ONO.sub.2], methoxy [OCH.sub.3], ethoxy [OCH.sub2CH.sub.3], fluoride [F], chloride [Cl], CF.sub.3, CCl.sub.3, phosphate, Rll, R12, OR11, OR12, OCOR11, OCOR12, O-sulfate [the sulfate conjugate], or O-glucoronidate [the glucoronic (AKA glucuronic) acid conjugates], with the proviso that at least one of R1-R10 or R13 or R14 is nitrooxy, R12, OR12, or OCOR12; and wherein OCOR means and R is Rl l or R12 wherein
- X can be O, CR13 or NR13;
- Y can be CO [a ketone still maintaining the 6 atom ring structure], CR14 or
- Z can be a single or a double bond.
- An isoflavonoid compound comprising the following structure:
- Rl, R2, R3, R4, R5, R6, R7, R8, R9, RIO, R13 and R14 may each be independently hydrogen, hydroxyl [OH], hydroxyalkyl, aminoalkyl, Bromide
- Y can be CO [a ketone still maintaining the 6 atom ring structure], CR14 or
- Alkoxynitroxy groups may be added to compounds using, for example, the methods taught in US Patent 5,861,426.
- Diazeniumdolates may be synthesized by various methods including, for example, the methods taught in US Patents 4,954,526,
- substitution of a hydroxyl group by a fluoride ion, a chloride ion, a bromide ion, a CF.sub.3 group, a CCl.sub.3 group, a CBr.sub.3, an alkyl chain of 1 to 18 carbon atoms, optionally substituted, optionally branched, or an alkoxy chain of 1 to 18 carbon atoms, optionally substituted, optionally branched is also contemplated and provided for, as such modifications to parent compounds are commonplace, known to increase drug stability without altering the mechanism of action, and are readily accomplished by one of skill in the art.
- Salts of the compounds described herein, including those preferred for pharmaceutical formulations, are also provided for in this invention.
- R12 is C S , aryl, heteroaryl or a derivative thereof, wherein said derivative is optionally substituted, optionally branched, may have one or more of the C atoms replaced by S, N or O, and containing one or more ONO.sub.2
- the present invention also provides for compounds having the general flavonoid structure:
- the present invention also provides for compounds having the general isoflavonoid structure:
- Rl, R2, R3, R4, R5, R6, R7, R8, R9, RIO, Rl 1, R12, R15, and R16 may each be independently hydrogen, hydroxyl [OH], hydroxyalkyl, aminoalkyl, Bromide (Br), Iodide (I), nitrooxy [ONO.sub.2], methoxy [OCH.sub.3], ethoxy [OCH.sub2CH.sub.3], fluoride [F], chloride [Cl], CF.sub.3, CCl.sub.3, phosphate, R13, R14, OR13, OR14, OCOR13, OCOR14, O-sulfate [the sulfate conjugate], or O-glucoronidate [the glucoronic (AKA glucuronic) acid conjugates], with the proviso that at least one of R1-R12 or R15 or R16 is nitrooxy, R14, OR14, or OCOR14; and wherein OCOR means and R is R13
- the present invention also provides for compounds having the general chalcone structure:
- Rl, R2, R3, R4, R5, R6, R7, R8, R9, RIO, and Rl l may each be independently hydrogen, hydroxyl [OH], hydroxyalkyl, aminoalkyl, Bromide (Br), Iodide (I), nitrooxy [ONO.sub.2], methoxy [OCH.sub.3], ethoxy [OCH.sub2CH.sub.3], fluoride [F], chloride [Cl], CF.sub.3, CCl.sub.3, phosphate, R13, R12, OR13, OR12, OCOR13, OCOR12, O-sulfate [the sulfate conjugate], or O-glucoronidate [the glucoronic (AKA glucuronic) acid conjugates], with the proviso that at least one of Rl-Rl 1 is nitrooxy, R12, OR12, or OCOR12; and wherein OCOR means and R is R12 or R13 wherein R13 is C MS ,
- NO-donating derivatives of cholesterol lowering compounds provided for in the invention include:
- the present invention also provides for compounds of the following general formula (XXXII)
- Rl, R2, R3, R4 may each be independently hydrogen, hydroxyl [OH], hydroxyalkyl, aminoalkyl, Bromide (Br), Iodide (I), nitrooxy [ONO.sub.2], methoxy [OCH.sub.3], ethoxy [OCH.sub2CH.sub.3], fluoride [F], chloride [Cl], CF.sub.3, CCl.sub.3, phosphate, Rll, R12, ORll, OR12, OCORll, OCOR12, O- sulfate [the sulfate conjugate], or O-glucoronidate [the glucoronic (AKA glucuronic) acid conjugates], with the proviso that at least one of R1-R4 is nitrooxy, R12, OR12, or OCOR12; and wherein OCOR means and R is Rl l or R12 wherein Rl l is C 1-18 , aryl, heteroaryl or a derivative thereof, wherein
- Rl is nitrooxy, R12, OR12, or OCOR12; and wherein OCOR means 0 ⁇ R 0 and R is R12
- R12 is C S , aryl, heteroaryl or a derivative thereof, wherein said derivative is optionally substituted, optionally branched, may have one or more of the C atoms replaced by S, N or O, and containing one or more ONO.sub.2
- the present invention also provides for the compound (XXXEV)
- Rl is nitrooxy, R12, OR12, or OCOR12; and wherein OCOR means 0 ,R 0 and R is R12
- R12 is C MS , aryl, heteroaryl or a derivative thereof, wherein said derivative is optionally substituted, optionally branched, may have one or more of the C atoms replaced by S, N or O, and containing one or more ONO.sub.2
- the present invention also provides for compounds of the following general formulae (XXXV)
- Rl, R2, R3 may each be independently hydrogen, hydroxyl [OH], hydroxyalkyl, aminoalkyl, Bromide (Br), Iodide ( ), nitrooxy [ONO.sub.2], methoxy [OCH.sub.3], ethoxy [OCH.sub2CH.sub.3], fluoride [F], chloride [Cl], CF.sub.3, CCl.sub.3, phosphate, Rll, R12, ORll, OR12, OCORll, OCOR12, O-sulfate [the sulfate conjugate], or O-glucoronidate [the glucoronic (AKA glucuronic) acid conjugates], with the proviso that at least one of R1-R3 is nitrooxy, R12, OR12, or
- OCOR12 and wherein OCOR means and R is Rll or R12 wherein Rll is C MS , aryl, heteroaryl or a derivative thereof, wherein said derivative is optionally substituted and optionally branched, and may have one or more of the C atoms replaced by S, N or O, and
- R12 is C S , aryl, heteroaryl or a derivative thereof, wherein said derivative is optionally substituted, optionally branched, may have one or more of the C atoms replaced by S, N or O, and containing one or more ONO.sub.2.
- the present invention also provides for compounds of the following general formulae (XXXVI)
- Rl, R2, R3 may each be independently hydrogen, hydroxyl [OH], hydroxyalkyl, aminoalkyl, Bromide (Br), Iodide (I), nitrooxy [ONO.sub.2], methoxy
- R12 is C S , aryl, heteroaryl or a derivative thereof, wherein said derivative is optionally substituted, optionally branched, may have one or more of the C atoms replaced by S, N or O, and containing one or more ONO.sub.2.
- the present invention also provides for compounds of the following general formulae (XXXVII)
- Rl, R2, R3 may each be independently hydrogen, hydroxyl [OH], hydroxyalkyl, aminoalkyl, Bromide (Br), Iodide (I), nitrooxy [ONO.sub.2], methoxy [OCH.sub.3], ethoxy [OCH.sub2CH.sub.3], fluoride [F], chloride [Cl], CF.sub.3, CCl.sub.3, phosphate, Rll, R12, ORll, OR12, OCORll, OCOR12, O-sulfate [the sulfate conjugate], or O-glucoronidate [the glucoronic (AKA glucuronic) acid conjugates], with the proviso that at least one of R1-R3 is nitrooxy, R12, OR12, or OCOR12; and wherein OCOR means and R is Rll or R12 wherein Rll is CM S , aryl, heteroaryl or a derivative thereof, wherein said derivative is optionally substituted and
- R12 is CM S , aryl, heteroaryl or a derivative thereof, wherein said derivative is optionally substituted, optionally branched, may have one or more of the C atoms replaced by S, N or O, and containing one or more ONO.sub.2.
- the present invention also provides for compounds of the following general formulae (XXXVIII)
- Rl, R2, R3 may each be independently hydrogen, hydroxyl [OH], hydroxyalkyl, aminoalkyl, Bromide (Br), Iodide (I), nitrooxy [ONO.sub.2], methoxy [OCH.sub.3], ethoxy [OCH.sub2CH.sub.3], fluoride [F], chloride [Cl], CF.sub.3,
- Rl l is C S , aryl, heteroaryl or a derivative thereof, wherein said derivative is optionally substituted and optionally branched, and may have one or more of the C atoms replaced by S, N or O, and
- R12 is C MS , aryl, heteroaryl or a derivative thereof, wherein said derivative is optionally substituted, optionally branched, may have one or more of the C atoms replaced by S, N or O, and containing one or more ONO.sub.2.
- the present invention also provides for compounds of the following general formula (XXXIX)
- Rll is C MS , aryl, heteroaryl or a derivative thereof, wherein said derivative is optionally substituted and optionally branched, and may have one or more of the C atoms replaced by S, N or O, and
- the present invention also provides for the compound (XL)
- Rl is nitrooxy, R12, OR12, or OCOR12; and wherein OCOR means and R is R12
- R12 is C MS , aryl, heteroaryl or a derivative thereof, wherein said derivative is optionally substituted, optionally branched, may have one or more of the C atoms replaced by S, N or O, and containing one or more ONO.sub.2.
- such compounds would be analogues or derivatives of stilbenes, such as resveratrol, of polyphenols, or of flavonoids, such as naringenin, or of other anti-oxidant, serum cholesterol decreasing or reverse cholesterol transport activating or HDL increasing compounds bound to nitric oxide donating moieties.
- such compounds would be analogues or derivatives of stilbenes, such as resveratrol, polyphenols, or flavonoids, such as naringenin, or of other anti-oxidant, serum cholesterol decreasing or reverse cholesterol transport activating or of HDL increasing compounds with one or more ONO.sub.2 groups, also referred to as nitric esters, organic nitrates, or nitrooxy groups, replacing hydroxyl groups of the parent compound.
- Another example of a compound provided for by the present invention is the reverse ester nitrooxy analogue of Naringenin, which with three hydroxyls substituted would be 5-Nitrooxy-pentanoic acid 4-[5,7-bis-(5-nitrooxy- pentanoyloxy)-4-oxo-chroman-2-yl]-phenyl ester. While not being limited to those compounds explicitly described herein, many more examples are provided in the example section of the present invention.
- trans-resveratrol source material to be used in the reaction could be obtained commercially from Bio-Stat Limited (Stockport, U.K.) or Sigma Chemical Co. (St. Louis, MO, USA), isolated from wine using the procedure of Goldberg et al. (1995) Am. J. Enol. Vitic. 46(2)-.159-165.
- trans-resveratrol may be synthesized according to the method of Toppo as taught in US patent 6,048,903 or from appropriately substituted phenols by means of a Wittig reaction modified by Waterhouse from the method of Moreno-Manas and Pleixats.
- naringenin to be used as an ingredient for synthesis reactions is a naturally occurring compound readily available from numerous commercial sources, or alternatively, isolatable using well known methods requiring no undue experimentation from natural sources such as citrus juice.
- the compounds may be used per se, but more preferably are presented with an acceptable carrier or excipient in the form of a pharmaceutically acceptable formulation.
- acceptable carrier or excipient in the form of a pharmaceutically acceptable formulation.
- formulations include those suitable for oral, rectal, topical, buccal and parenteral (e.g. subcutaneous, intramuscular, intradermal, or intravenous) administration, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used.
- Formulations suitable for oral administration may be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of the compound as powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion.
- such formulations may be prepared by any suitable method of pharmacy which includes the step of bringing into association the active compound and the carrier or excipient (which may constitute one or more accessory ingredients).
- the carrier must be acceptable in the sense of being compatible with the other ingredients of the formulation and must not be deleterious to the recipient.
- the carrier may be a solid or a liquid, or both, and is preferably formulated with the compound as a unit- dose formulation, for example, a tablet, which may contain from 0.05% to 95% by weight of the active compound.
- Other pharmacologically active substances may also be present including other compounds.
- the formulations of the invention may be prepared by any of the well known techniques of pharmacy consisting essentially of admixing the components.
- Formulations suitable for buccal (sub-lingual) administration include lozenges comprising a compound in a flavored base, usually sucrose and atacia or tragacanth, and pastilles comprising the compound in an inert base such as gelatin and glycerin or sucrose and acacia.
- Formulations of the present invention suitable for parenteral administration comprise sterile aqueous preparations of the compounds, which are approximately isotonic with the blood of the intended recipient. These preparations are administered intravenously, although administration may also be effected by means of subcutaneous, intramuscular, or intradermal injection. Such preparations may conveniently be prepared by admixing the compound with water and rendering the resulting solution sterile and isotonic with the blood.
- Injectable compositions according to the invention will generally contain from 0.1 to 5% w/w of the active compound.
- Formulations suitable for rectal administration are presented as unit-dose suppositories. These may be prepared by admixing the compound with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.
- one or more conventional solid carriers for example, cocoa butter
- the amount of active compound administered will, of course, be dependent on the subject being treated, the subject's weight, the manner of administration and the judgment of the prescribing physician.
- a dosing schedule will generally involve the daily or semi-daily administration of the encapsulated compound at a perceived dosage of lug to lOOOmg.
- Encapsulation facilitates access to the site of action and allows the administration of the active ingredients simultaneously, in theory producing a synergistic effect.
- physicians will readily determine optimum dosages and will be able to readily modify administration to achieve such dosages.
- the term "the compounds” or “the compound” will refer to any of the compounds provided for in the present invention.
- the fully nitrated product (l,3-BIS-nitrooxy-5-[(E)-2-(4-nitrooxy-phenyl)-vinyl)- benzene) and the partially nitrated products (wherein any of the hydroxyl groups are independently replaced by ONO.sub.2 groups) are purified and isolated by chromatography on silica gel.
- the fully nitrated product (piceatannol tetranitrate) and the partially nitrated products (wherein any of the hydroxyl groups are independently replaced by ONO.sub.2 groups) are purified and isolated by cbromatography on silica gel.
- EXAMPLE 4 Preparation of isoliquiritigenm trinitrate To a solution of 1 mmol of 4, 2', 4'- trihydroxychalcone (synonym: isoliquiritigenm) in 5 ml of dry THF at 25°C is added 3 mmol of SOCl(NO.SUB.3) or SO(NO.SUB.3).sub.2. After 1 hr, Et.sub.2O (diethyl ether) is added and the solution is washed with water, dried and evaporated. The fully nitrated product isoliquiritienin trinitrate and the partially nitrated products (wherein any of the hydroxyl groups are independently replaced by ONO.sub.2 groups) are purified and isolated by chromatography on silica gel.
- EXAMPLE 6 Preparation of quercetin pentanitrate To a solution of 1 mmol of 3, 5, 7, 3', 4'- pentahydroxyflavone (synonym: quercetin) in 5 ml of dry THF at 25°C is added 5 mmol of SOCl(NO.SUB.3) or SO(NO.SUB.3).sub.2. After 1 hr, Et.sub.2O (diethyl ether) is added and the solution is washed with water, dried and evaporated. The fully nitrated product quercetin pentanitrate and the partially nitrated products (wherein any of the hydroxyl groups are independently replaced by ONO.sub.2 groups) are purified and isolated by chromatography on silica gel.
- quercetin pentanitrate To a solution of 1 mmol of 3, 5, 7, 3', 4'- pentahydroxyflavone (synonym: quercetin) in 5 ml of dry T
- EXAMPLE 7 Preparation of N-(3,5-Bis-nitrooxy-phenyl)-N'-(4-nitrooxy-phenyl)- hydrazine To a solution of 1 mmol of 5-[N'-(4-hydroxy-phenyl)-hydrazino]-benzene-l,3-diol in 5 ml of dry THF at 25°C is added 3 mmol of SOCl(NO.SUB.3) or SO(NO.SUB.3).sub.2. After 1 hr, Et.sub.2O (diethyl ether) is added and the solution is washed with water, dried and evaporated.
- EXAMPLE 24 Preparation of 3,4,5-tris-nitrooxy-N-phenyl-benzamide To a solution of 1 mmol of 3,4,5-trihydroxy-N-((Z)-l-methylene-but-2-enyl)- benzamide (synonym: gallanilide) in 5 ml of dry THF at 25°C is added 3 mmol of SOCl(NO.SUB.3) or SO(NO.SUB.3).sub.2. After 1 hr, Et.sub.2O (diethyl ether) is added and the solution is washed with water, dried and evaporated.
- EXAMPLE 25 Preparation of l-(2,4-bis-nitrooxy- ⁇ henyl)-2-phenyl-ethanone To a solution of 1 mmol of l-(2,4-hydroxy-phenyl)-2-phenyl-ethanone (synonym: benzyl 2,4-dihydroxyphenyl ketone) in 5 ml of dry THF at 25°C is added 2 mmol of SOCl(NO.SUB.3) or SO(NO.SUB.3).sub.2. After 1 hr, Et.sub.2O (diethyl ether) is added and the solution is washed with water, dried and evaporated.
- Et.sub.2O diethyl ether
- the fully nitrated product l-(2,4-bis-nitrooxy-phenyl)-2-phenyl-ethanone and the partially nitrated products are purified and isolated by chromatography on silica gel.
- EXAMPLE 32 Preparation of l-benzyl-2,4-bis-nitrooxy-benzene To a solution of 1 mmol of 4-benzyl-benzene-l,3-diol (synonym: 1,3 benzenediol 3- phenyl methyl) in 5 ml of dry THF at 25°C is added 2 mmol of SOCl(NO.SUB.3) or SO(NO.SUB.3).sub.2. After 1 hr, Et.sub.2O (diethyl ether) is added and the solution is washed with water, dried and evaporated.
- EXAMPLE 39 Preparation of 5,7-bis-nitrooxy-2-(4-nitrooxy-phenyl)-chroman-4-one To a solution of 1 mmol of 5,7-dihydroxy-2-(4-hydroxy-phenyl)-chroman-4-one (Synonym: naringenin) in 5 ml of dry THF at 25°C is added 3 mmol of SOCl(NO.SUB.3) or SO(NO.SUB.3).sub.2. After 1 hr, Et.sub.2O (diethyl ether) is added and the solution is washed with water, dried and evaporated.
- EXAMPLE 40 Preparation of 5,7-bis-nitrooxy-2-(4-nitrooxy-phenyl)-chromen-4-one To a solution of 1 mmol of 5,7-dihydroxy-2-(4-hydroxy-phenyl)-chromen-4-one (Synonym: apigenin) in 5 ml of dry THF at 25°C is added 3 mmol of SOCl(NO.SUB.3) or SO(NO.SUB.3).sub.2. After 1 hr, Et.sub.2O (diethyl ether) is added and the solution is washed with water, dried and evaporated.
- EXAMPLE 41 Preparation of 5,7-bis-nitrooxy-3-(4-nitrooxy-phenyl)-chromen-4-one To a solution of 1 mmol of 5,7-dihydroxy-3-(4-hydroxy-phenyl)-chromen-4-one (Synonym: genistein) in 5 ml of dry THF at 25°C is added 3 mmol of SOCl(NO.SUB.3) or SO(NO.SUB.3).sub.2. After 1 hr, Et.sub.2O (diethyl ether) is added and the solution is washed with water, dried and evaporated.
- EXAMPLE 45 Preparation of l-(4-hydroxy-2,6-bis-nitrooxy-phenyl)-3-(4-nitrooxy- phenyl)-propan- 1 -one
- Et.sub.2O diethyl ether
- the fully nitrated product 1 -(4-hydroxy-2,6-bis-nitrooxy-phenyl)-3 -(4-nitrooxy-phenyl)-propan- 1 -one and the partially nitrated products are purified and isolated by chromatography on silica gel.
- EXAMPLE 47 Preparation of l-nitrooxy-4-((E)-3-phenyl-propenyl)-benzene To a solution of 1 mmol of 4-((E)-3-phenyl-propenyl)-phenol in 5 ml of dry THF at 25°C is added 1 mmol of SOCl(NO.SUB.3) or SO(NO.SUB.3).sub.2. After 1 hr, Et.sub.2O (diethyl ether) is added and the solution is washed with water, dried and evaporated. The nitrated product l-nitrooxy-4-((E)-3-phenyl-propenyl)-benzene is purified and isolated by chromatography on silica gel.
- EXAMPLE 50 Preparation of 5-hydroxy-2-(4-hydroxyphenyl)-7-(2-O-al ⁇ ha-L- rhamnopyranosyl-beta-D-glucopyranosyloxy)-4-chromanon dinitrate
- To a solution of 1 mmol of 5-hydroxy-2-(4-hydroxyphenyl)-7-(2-O-alpha-L- rhamnopyranosyl-beta-D-glucopyranosyloxy)-4-chromanon (synonym: naringin) in 5 ml of dry THF at 25°C is added 2 mmol of SOCl(NO.SUB.3) or SO(NO.SUB.3).sub.2.
- EXAMPLE 52 Preparation of 5-(4-fluoro-phenyl)-2-isopropyl-4- ⁇ henyl-l-((3R,5R)- 3,5,7-tris-nitrooxy-7-oxo-heptyl)-lH-pyrrol-l-yl]-3-carboxylic acid phenylamide
- To a solution of 1 mmol of (3R,5R)-7-[2-(4-fluoro-phenyl)-5-isopropyl-3-phenyl-4- phenylcarbamoyl-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Synonym: atorvastatin; Parke-Davis) in 5 ml of dry THF at 25°C is added 3 mmol of SOCl(NO.SUB.3) or SO(NO.SUB.3).sub.2.
- EXAMPLE 53 Preparation of (E)-(3R,5S)-7-[4-(4-fluoro-phenyl)-2,6-diisopropyl-5- methoxymethyl-pyridin-3-yl]-l,3,5-tris-nitrooxy-hept-6-en-l-one
- To a solution of 1 mmol of (E)-(3R,5S)-7-[4-(4-fluoro-phenyl)-2,6-diisopro ⁇ yl-5- methoxymethyl-pyridin-3-yl]-3,5-dihydroxy-hept-6-enoic acid (Synonym: cerivastatin; Bayer) in 5 ml of dry THF at 25°C is added 3 mmol of SOCl(NO.SUB.3) or SO(NO.SUB.3).sub.2.
- EXAMPLE 60 Method for glucoronidating compounds of the invention This example describes the method of preparing glucoronidated compounds of the invention.
- a dinitrated version of resveratrol, 3,4'-nitrooxy-5- hydroxy resveratrol (50-1000 ⁇ M) prepared as in Example 1 and 10 ⁇ l of human intestinal, 25 ⁇ l of colon or 10 ⁇ l of liver microsomes (200, 400, 200 ⁇ g of protein, respectively), 20 of ⁇ l recombinant UDP-glucuronosyltransferase (400 ⁇ g of protein) in a final volume of 500 ⁇ l of 50 mM Tris HC1 buffer (pH 7.8) with 10 mM MgCl 2 are preincubated for 5 min at 37°C.
- the reactions are initiated by the addition of 1 mM 5'- diphosphoglucuronic acid.
- the reaction mixtures are incubated at 37°C for 60 min.
- the samples are cooled on ice and subjected to solid-phase extraction using oasis Hydrophilic-Lipophilic Balance lcc C 18 extraction cartridges (Waters Corp, Milford, MA).
- the cartridges are washed with 1-ml methanol and equilibrated with 1-ml water. After loading 0.5 ml of the sample, the cartridges are washed with 5% methanol and eluted with 2 ml of 100% methanol.
- the methanol eluate is dried under N 2 gas at 40°C, and the sample is redissolved in 250 ⁇ l of mobile phase for HPLC analysis.
- This example describes the method of preparing sulfated compounds of the invention. h this specific example, a dinitrated version of resveratrol, 3,4'-nitrooxy-5-hydroxy resveratrol prepared as in Example 1 is sulfated by a sulfofransferase enzyme using a previously described ion-pair extraction method (Varin et al. 1987. Anal. Biochem. 161:176-180).
- the typical reaction mixture contains 0.1 to 200 ⁇ M of 3,4'-nitrooxy-5- hydroxy resveratrol, 1 ⁇ M [ 35 S]PAPS and 2.5 ⁇ l of pooled human liver cytosol (50 ⁇ g of protein), 2.5 ⁇ l of human jejunal cytosol (30 ⁇ g), Caco-2 cytosol (225 ⁇ g) or 0.25 ⁇ l recombinant sulfofransferase in 33 mM Tris-HCl buffer, pH 7.4, with 8 mM dithiothreitol and 0.0625% bovine serum albumin in a total volume of 100 ⁇ l.
- rats are sacrificed by decapitation and the livers excised. 1 g each of the livers is homogenized in 5 ml of homogenization medium (0.1 M KH.sub.2 PO.sub.4, pH 7.4, 0.1 mM EDTA and 10 mM .beta.-mercaptoethanol).
- the homogenate is centrifuged at 3,000.times.g for 10 min. at 4.degree. C. and the supernatant thus obtained is centrifuged at 15,000.times.g for 15 min. at 4,degree. C. to obtain a supernatant.
- the supernatant is put into an ultracentrifuge tube (Beckman) and centrifuged at 100,000.times.g for 1 hour at 4.degree. C.
- microsomal pellets which are then suspended in 3 ml of the homogenization medium and centrifuged at 100,000.times.g for 1 hour at 4.degree. C.
- the pellets thus obtained are suspended in 1 ml of the homogenization medium.
- the concentration of proteins in the resulting suspension is detennined by Lowry's method and then adjusted to 4 to 8 mg/ml.
- the resulting suspension is stored in a deep freezer (Biofreezer, Forma Scientific Inc.).
- ACAT activity is calculated as picomoles of cholesteryl oleate synthesized per min. per mg protein (pmoles/min mg protein).
- ACAT activities observed rat groups that have received compounds of the invention are lower than those of the control group.
- EXAMPLE 63 Determination of inhibition of HMG-CoA reductase The potency of inhibition of HMG-CoA reductase by compounds of the invention may be determined using known methods, such as that taught in US Patent 5,877,208. That method is summarized below.
- Rats are sacrificed by decapitation and the livers are excised and immediately placed in an ice-cold homogenization medium (50 mM KH.sub.2 PO.sub.4 (pH 7.0), 0.2M sucrose, 2 mM dithiothreitol (DTT)).
- the livers are homogenized in the homogenization medium (2 ml medium/g of the liver) with a Waring blender for 15 sec. (three strokes with a motor-driven Teflon pestle in a Potter-Elvehjem type glass homogenizer).
- the homogenate is centrifuged at 15,000.times.g for 10 min. and the supernatant thus obtained is centrifuged at 100,000.times.g for 75 min.
- HMG-CoA reductase The activity of HMG-CoA reductase is determined by employing radiolabeled 14C HMG-CoA, in accordance with the method of Shapiro et al. (Biochemica et Biophysica Acta, 370, 369-377(1974)) as follows.
- the enzyme in the supernatant containing the microsome obtained in (Step 1) is activated at 37.degree. C. for 30 min.
- Added to a reaction tube is 20 .mu.l of HMG- CoA reductase assay buffer (0.25M KH.sub.2 PO.sub.4 (pH 7.0), 8.75 mM EDTA, 25 mM DTT, 0.45M KCl and 0.25 mg/ml BSA), 5 .mu.l of 50 mM NADPH, 5 .mu.l of radiolabeled 14C HMG-CoA (0.05 .mu.Ci/tube, final cone.
- EXAMPLE 64 Determination of activation of PPAR by compounds of the invention The ability of compounds of the invention to modify the activity of PPARgamma and PPARalpha are determined by several known methods, such as those described below, which were previously taught in US Patent 6,369,098.
- NF-kappaB Human endothelial cells and vascular smooth muscle cells (VSMC) are known to express both PPARgamma and PPARalpha (Neve BP et al. Biochem Pharmacol., 60:1245-1250 (2000)).
- VSMC vascular smooth muscle cells
- isolated human peripheral T lymphocytes from normal healthy donors or a mammalian cell line such as a Jurkat T cell line transfected with the PPARalpha and/or the PPARgamma expression vector may be used in these experiments.
- One of these selected cell types is stimulated with one or more of: phytohemagglutinin/phorbol-12-myristate- 13 -acetate (PHA/PMA), TNF- alpha, interferon- gamma or other factor that activates NF-kappaB.
- PHA/PMA phytohemagglutinin/phorbol-12-myristate- 13 -acetate
- TNF- alpha TNF- alpha
- interferon- gamma or other factor that activates NF-kappaB Activation of NF- kappaB is determined by elecfrophoretic mobility shift assay similar to that previously described (Rossi A et al. Proc Natl Acad Sci USA, 94:746-50 (1997)).
- Preincubation of the same cells with 5 micromolar of a compound of the invention 2 hours prior to addition of an activator of NF-kappaB inhibits the activation of NF-kappaB that is otherwise observed in
- Isolated human peripheral T lymphocytes from normal healthy donors or a mammalian cell line such as a Jurkat T cell line transfected with the PPARalpha and/or the PPARgamma expression vector are stimulated with one or more of PHA/PMA, TNF-alpha, interferon-gamma or other factor that activates NFAT.
- Transcriptional activation of NFAT is determined by elecfrophoretic mobility shift assay similar to that described by Yang et al. J Biol Chern.; 275:4541-4 (2000).
- Preincubation of the same cells with 5 micromolar of a compound of the invention for 2 hours prior to addition of an activator of NFAT inhibits the activation of NFAT otherwise observed in the absence of said compound.
- Isolated human T lymphocytes or a mammalian cell line such as a Jurkat T cell line transfected with a PPARalpha and/or a PPARgamma expression vector is stimulated with one or more of PHA/PMA, TNF-alpha, interferon-gamma or some other factor that activates induction of IL-2 gene expression.
- Production of IL-2 is determined measuring the concentration of IL-2 in the supernatant from cells using Endogen kits (Wolbum), as described by Yang et al. J Biol Chern., 275:4541-4 (2000).
- Preincubation of the same cells with 5 micromolar of a compound of the invention for 12 hours prior to addition of an activator of IL-2 production inhibits the activation of IL-2 production otherwise observed in the absence of said compound.
- EXAMPLE 65 Method of determining the ABCA-1 activating ability of compounds of the invention
- Plasmid pGL3-Basic (Promega, Madison, Wis.; Cat. #E1751) is used as a control plasmid containing the promoterless luciferase gene.
- the reporter construct containing the ABCA-1 promoter and luciferase gene is made by cloning a genomic fragment from the 5' flanking region of the ABCA-1 gene (hAPRl 5' promoter, corresponding to nucleotides 1080-1643 of SEQ ID NO: 3) into the Sad site of the GL3 -Basic plasmid to generate plasmid GL-6a.
- plasmid GL-6a is digested with Spel and Acc65I.
- Geneporter reagent Gene Therapy Systems, San Diego, Calif.; Cat. #T201007.
- 0.1 .mu.g of pCMV.beta. plasmid DNA (Clontech, Palo Alto, Calif, Cat. #6177-1) is added as a control for transfection efficiency.
- the culture medium is replaced with serum-free DMEM/BSA in the presence or absence of acetylated LDL (100 .mu.g/ml) and incubated for 24 hours.
- Compounds of the invention demonstrate increased ABCA-1 gene expression in this assay.
- the cells are harvested and the Luciferase activity is measured with a standard protocol employing a commercially available luciferase assay.
- Spent media exposed to the cells for 36 hours is also assayed for its content of APO Al protein using western blot analysis.
- Increased luciferase activity in the cell lysate or spent media indicates compounds of the invention with apolipoprotein Al expression inducing activity.
- Vasodilative activity is also determined in isolated rat aorta measuring the inhibition of the contraction induced by epinephrine in the tissue prepared in accordance with the method described by Reynolds et al. (J. Pharmacol. Exp. Therap. 252, 915, 1990).
- Increased relaxation induced by the addition of compounds of the invention demonstrates the vasodilation activity and usefulness of the compounds for the treatment or prevention of numerous disorders associated with hypertension, for example cardiovascular disorders.
- compounds of the invention are dissolved in an appropriate solvent and phosphate buffer at pH 7.4 and incubated in a 37°C water bath.
- the NO release rate is measured periodically by flushing the solution with inert nitrogen gas and then sweeping newly generated NO into a chemiluminescence detector and integrating the signal produced over the next 4-7 minutes.
- Increased NO release relative to negative controls, potentially appropriate negative controls being for example hydroxylated rather than nitrated versions of the same compounds demonstrates the NO releasing activity and usefulness as a treatment or prevention for disorders, disease or conditions associated with hypertension, for example cardiovascular disorders.
- antioxidant performance of compounds of the invention is demonstrated by measuring the extent of low density lipoprotein hydroxyperoxide by copper catalyzed autoxidation using a published dye based color assay (FOX Assay, see Zadeh, "Methods in Enzymology", 300, 58 (1999)). Samples containing only LDL and copper sulfate without test materials, serve as a positive control for comparison with identical mixtures containing test materials.
- Esterbauer (Esterbauer, H., Striegl, G., Puhl, H., Rotheneder, M., "Continuous monitoring of in vitro oxidation of human low density lipoprotein", Free Radic. Res. Commun, 1989; 6(1): 67-75) may be used, with some modification as follows:
- the compound is dissolved with an appropriate solubilizing agent in a phosphate buffer solution (PBS, 0.15 M NaCl-0.05 M Na Phosphate Buffer-pH 7.4).
- PBS 0.15 M NaCl-0.05 M Na Phosphate Buffer-pH 7.4
- concentration is noted (approximately 30-60 mu.g/mL of extract to be measured).
- a blank sample made with 100 mu.L PBS and 900 mu.L oxidizing buffer is also prepared. Each solution is then transferred to a 1 cm quartz cuvette, and the cuvette is placed into thermostat (37 degrees C).
- An HP-8452A Diode Array Spectrophotometer measures optical density at 234 nm (OD sub 234), making a measurement every 5 minutes. The lag time for oxidation is calculated as the maximum of the first derivative of the optical density curve.
- a standard containing ascorbic acid is run with each assay.
- EXAMPLE 73 Measurement and comparison of HDL, LDL, VLDL and triglyceride levels Compounds or the dosing vehicle alone are administered daily to chow fed male Sprague-Dawley rats or female obese Zucker rats for seven days in the morning by oral gavage in 1.5% carboxymethylcellulose/0.2% Tween-20 (dosing vehicle). Animals are weighed daily and allowed free access to rodent chow and water throughout the study. Orbital blood samples are obtained following a six-hour fast prior to the initial dose and also following the seventh dose.
- EXAMPLE 74 Measurement and comparison of HDL, LDL, VLDL and triglyceride levels in humans in response to administration of the compounds Compounds of the invention are administered daily to human subjects. Other dietary uptake is monitored and held constant between individuals. Blood samples are taken on the day 0, prior to commencing the administration of the compounds, and once weekly for 3 to 6 months.
- EXAMPLE 75 Measurement of Atherosclerotic Lesion Size Using Proteoglycan- Binding-Defective LDL
- EXAMPLE 76 Measurement of reduced hypertension in living animals A pressure transducer is connected to the right carotid artery via a catheter containing heparinized saline. The mean arterial pressure and heart rate are recorded. The rats are anesthetized with nembutal at an initial dose of 35 mg/kg body weight with additional smaller injections as necessary. The compounds are dissolved in a pharmaceutical carrier (such as Abbott's 5% dextrose USP) and injected into the rats via a catheter in the right femoral vein. Positive controls that may be employed include sodium nitroprusside and NaNO2, while NaNO.SUB.3 may be employed as a negative control.
- a pharmaceutical carrier such as Abbott's 5% dextrose USP
- the results will show that the compounds provided for in the invention are potent anti-hypertensives, that decreases blood pressure significantly.
- the peak value of the blood pressure decrease should take a short time to reach, for example approximately one minute, after injection and the blood pressure should start to rise again soon thereafter and should have totally recovered within about approximately 10 to 15 minutes.
- EXAMPLE 79 Measurement of platelet anti-aggregating activity Platelet anti-aggregating activity may be evaluated in vitro on human platelets stimulated by thrombin in accordance with the method described by Bertele et al. (Science 220, 517, 1983).
- Male rats (Charles River, CRL:CD(SD), 400-450 g) are anesthetized with Na pentabarbital (65 mg/kg, Vet Labs, Limited, Inc., Lenexa, KA). Two incisions are made to expose both jugular veins. Using an infusion pump (Harvard Apparatus, South Natick, Mass.) and a 5 cc syringe with a 19 g. butterfly, the test compound or vehicle is infused into the left jugular vein at a rate of 0.39 ml min for 3 min.
- EXAMPLE 82 Measurement of the in vivo anti-psoriatic effectiveness
- a topical formulation comprising a compound of the invention is administered to the affected area of human patients suffering from psoriasis.
- a control formulation containing none of the compound of the invention, is applied to a comparable area of the patient.
- the effectiveness of the compoxmd is determined by analyzing the improvement in inflammation and decrease in proliferative cells at the site at which the compound is applied compared to the site at which control formulation is applied at 3 and 7 days following administration.
- EXAMPLE 88 Measurement of the cancer chemopreventative activity
- C3H/10T1/2 clone 8 cells are treated with a compound of the invention by the method of Mondal (Mondal et al. 1976. Cancer Res. 36:2254-2260).
- the cells in culture are treated with 3-methylcholanthrene for 24 hours, followed by washing a five days of incubation in fresh medium.
- TPA is subsequently added to the medium, with or without the test compound. Seven weeks after confluency is reached, fixation with methanol and staining with Giemsa reveals Type II and III transformed foci, which are scored to demonstrate effectiveness of inhibition of two-stage transformation by the test compound.
- EXAMPLE 89 Method for synthesizing fluoride derivatives of compounds of the invention, including stilbenes, polyphenols and flavonoids prior to the replacement of a hydroxyl group or groups with a nitrooxy group or groups.
- a stainless steel lined autoclave of 400 mL capacity is charged with 250 millimoles of 5-[(E)-2-(4-hydroxy-phenyl)-vinyl]-benzene-l,3-diol (synonym: resveratrol) and evacuated.
- 500 millimoles of sulfur oxytetrafluoride is introduced, and the reaction mixture is shaken and heated at 150 °C for 9 hours.
- the gaseous product principally sulfuryl fluoride, is distilled at -49°C to -44° C. The remainder is washed with aqueous 5% sodium hydroxide and with water.
- this liquid Upon distillation this liquid will be found to contain a mixture containing the fully and partially fluoridated products, 3- fluoro-5-[(E)-2-(4-hydroxy-phenyl)-vinyl]- ⁇ henol, 5-[(E)-2-(4-fluoro-phenyl)-vinyl]- benzene-l,3-diol, 4-[(E)-2-(3,5-difluoro-phenyl)-vinyl]-phenol, and l,3-difluoro-5- [(E)-2-(4-fluoro-phenyl)-vinyl-benzene.
- the various products are purified and isolated by chromatography on silica gel.
- the compound may be further modified to contain a nitrooxy group, as described in Examples 1 through 59. This method works without undue experimentation for the addition of fluorides to any of the compounds of the invention.
- X is NH and Rl-10 are each independently chosen from H or OH
- These compounds of the invention are useful as intermediary compounds from which may be subsequently synthesized nitrooxy derivatives as described in Examples 1-59, as well as nitrooxy derivates that may be additionally modified to comprise phosphate, fluoride, ester groups, and other modifications.
- An example intermediary compound, N-(3,5-dihydroxy- ⁇ henyl)-4-hydroxy-benzamide, which is useful in the subsequent preparation of a nitrooxy derivative thereof, is synthesized by the following method.
- reaction is performed with 5-aminomethyl-benzene- 1,3-diol employed in place of 5-amino-benzene-l,3-diol, resulting in the synthesis of N-(3,5- dihydroxy-benzyl)-4-hydroxy-benzamide.
- This synthesis demonstrates the method for the synthesis of compounds wherein X is NHCH.sub.2 for the general formula of this example.
- modification to the alkyl group of the phenol will result in the same modification to the linker of the resulting product.
- substitution of the R group connected to the amino reagent provided for in this synthesis description i.e. substitution of the benzene 1,3-diol group of 5-amino- benzene- 1,3-diol
- substitution of the benzene 1,3-diol group of 5-amino- benzene- 1,3-diol by for example fluorinated, brominated, chlorinated, or acetylated aryl groups, or by heteroaromatic aryl groups, or by Cl-18 alkyl groups, or by bicyclic aryl groups, or the like, will result in appropriately modified products, as is obvious to one of skill in the art.
- Polyphenol compounds contemplated in the invention include compounds comprising two aromatic rings connected to one another by a linking group, wherein said linking group comprises a carbon atom single bonded to a nitrogen atom.
- Polyphenol compounds of the following general formula are easily synthesized by this reaction, from readily available starting reagents.
- X is CH.sub.2 and Y is NH or, X is NH and Y is CH.sub.2 and Rl-10 are each independently chosen from H or OH
- These compounds of the invention are useful as intermediary compounds from which may be subsequently synthesized nitrooxy derivatives as described in Examples 1-59, as well as nitrooxy derivates that may be additionally modified to comprise phosphate, fluoride, ester groups, and other modifications.
- An example intermediary compound, 5-(4-hydroxy-benzylamino)-benzene 1,3-diol, which is useful in the preparation of a nitrooxy derivative thereof, is synthesized by the following method.
- reaction is performed with 4-hydroxy-phenyl-acetaldehyde employed in place of 4-hydroxy-benzaldehyde, resulting in the synthesis of 5-[2-(4- hydroxy-phenyl)-ethylamino]-benzene- 1,3-diol.
- This synthesis demonstrates the method for the synthesis of compounds wherein X is (CH.sub.2). sub.2 and Y is NH for the general formula of this example.
- modification to the alkyl group of the phenol will result in the same modification to the linker of the resulting product.
- Products synthesized by this method may be advantageously employed as intermediary compounds useful for the synthesis of NO-donating, nitrooxy derivative compounds of the invention.
- These compounds of the invention are useful as intermediary compounds from which may be subsequently synthesized nitrooxy derivatives as described in Examples 1-59, as well as nitrooxy derivates that may be additionally modified to comprise phosphate, fluoride, ester groups, and other modifications.
- An example intermediary compound, 5-(4-hydroxy-phenoxymethyl)-benzene 1,3-diol, which is useful in the preparation of a nitrooxy derivative thereof, is synthesized by the following method.
- Products synthesized by this method may be advantageously employed as intermediary compounds useful for the synthesis of NO-donating, nitrooxy derivative compounds of the invention..
- Polyphenol compounds contemplated in the invention include compounds comprising two aromatic rings connected to one another by a linking group, wherein said linking group comprises a carbon atom double bonded to a nitrogen atom.
- Polyphenol compounds of the following general formula are easily synthesized by this reaction, from readily available starting reagents.
- X is CH and Y is CH and Rl-10 are each independently chosen from H or OH
- acetyl groups in place of hydroxyl groups for some compounds of the invention, as certain acetyls can alter the degree of lipophilicity and thus modify the rate of metabolism and half life of a compound in the serum.
- replacing one or more of the hydroxyl groups of resveratrol to form an acetate derivative of resveratrol reduces the rate of metabolism and extends the half life in the serum.
- the synthesis of acetate derivatives of resveratrol which advantageously occurs prior to addition of one or more nitrate (i.e. ONO.sub.2, or nitric ester) groups, and prior to addition of phosphate groups if such is desired, but following fluoridation, is described herein.
- Resveratrol (0.5 millimoles) is dissolved in dry dichloromethane (5ml). Dry pyridine in excess is added followed by 1 millimole of acetic anhydride. The resulting solution is stirred at room temperature for 5 hours. The reaction mixture is concentrated and redissolved in dichloromethane (20 ml). The organic layer was washed with a hydrogen chloride solution (0.1 M, 10ml), sodium bicarbonate (saturated, 10ml), and brine. The organic layer was dried with magnesium sulfate, filtered and concentrated to give a mixture in high yield and purity of resveratrol acetate derivatives wherein one, two or all three of the hydroxyl groups was replaced by acetate. The various products are purified and isolated by chromatography on silica gel.
- the acetate derivatives are also synthesized using an acetyl halide (such as acetyl chloride) or activated acetate (such as the N-hydroxysuccinimide ester).
- acetyl halide such as acetyl chloride
- activated acetate such as the N-hydroxysuccinimide ester.
- Other esters of compounds of the invention are similarly synthesized using the same procedure, replacing the acetic anhydride with another activated ester or acid halide. Examples of such esters which can be substituted for any hydroxyl group on any of the compounds contemplated by the invention are described by the formula:
- EXAMPLE 97 Method of synthesizing methoxy and ethoxy derivatives of compounds of the invention, used as intermediary compounds from which are synthesized nitrooxy derivatives, which are all compounds contemplated by the invention It may be advantageous with some compounds of the invention to have methoxy (OCH.sub.3) or ethoxy (OCH.sub.2CH.sub.3) groups present for the R group, as methoxy and ethoxy groups are known to be lipophilic and thus may modify the half life of a drug in vivo without reducing its activity.
- Anti-cancer activity of compounds of the invention is demonstrated, as taught in US Patent 5,145,839, using the following animal model of cancer, and treating with compounds of the invention.
- Ehrlich ascitic cells (20-22 grams, Charles River breeding) are distributed at random in sets of 10. Each set receives, respectively: Set I Control, tumor cells and NaCl isotonic solution (0.2 ml/mouse, twice/day, i.p. route)
- mice bearing tumor cells receive a compound of the invention 0.2 ml/mouse, twice/day, delivered i.p.
- mice bearing tumor cells receive a compound of the invention: 0.2 ml/mouse twice/day, administered i.m.
- hypoglycemic activity of compounds of the invention is demonstrated using methods taught in US Patent 6,410,596. This test demonstrates the activity of the compounds of the invention in reducing plasma glucose levels in C57BL ks diabetic (db/db) mice, i.e., an art-recognized model of non-insulin dependent diabetes mellitus (NEDDM).
- NEDDM non-insulin dependent diabetes mellitus
- the product is made using another activated carboxylic acid analogue (acid chloride, anhydride, etc).
- Reverse ester nitro oxy derivatives may be synthesized by this method for all compounds contemplated by the invention, for example, the method of synthesis provided for naringenin may be applied to any of the starting compounds of examples 1 through 59, which will then subsequently give rise to the reverse ester nitro oxy derivative of said starting compound rather than to the nitro oxy derivative of said starting compound.
- EXAMPLE 103 Alternate preparation of 5-Nitrooxy-pentanoic acid 4-[5,7-bis-(5- nitrooxy-pentanoyloxy)-4-oxo-chroman-2-yl]-phenyl ester
- the product is made using another activated carboxylic acid analogue (acid chloride, anhydride, etc).
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WO2017041701A1 (en) * | 2015-09-07 | 2017-03-16 | 浙江华海药业股份有限公司 | Nitric oxide-releasing prodrug molecule |
US10456405B2 (en) | 2015-09-07 | 2019-10-29 | Zhejiang Huahai Pharmaceutical Co., Ltd | Nitric oxide-releasing prodrug molecule of substituted quinazolines |
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CN108069954B (en) * | 2017-03-03 | 2018-11-23 | 上海华汇拓医药科技有限公司 | The quinazolinones of the donor containing NO |
Also Published As
Publication number | Publication date |
---|---|
MXPA06003839A (en) | 2006-07-03 |
EP1670484A1 (en) | 2006-06-21 |
JP2007509842A (en) | 2007-04-19 |
CA2545479A1 (en) | 2005-04-14 |
US20050080024A1 (en) | 2005-04-14 |
WO2005032559A8 (en) | 2005-06-16 |
KR20060111494A (en) | 2006-10-27 |
AU2004277291A1 (en) | 2005-04-14 |
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