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WO2006024545A1 - Composes bicycliques naturels condenses et utilisation de ceux-ci comme inhibiteurs de parp et des processus inflammatoires a mediation parp - Google Patents

Composes bicycliques naturels condenses et utilisation de ceux-ci comme inhibiteurs de parp et des processus inflammatoires a mediation parp Download PDF

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WO2006024545A1
WO2006024545A1 PCT/EP2005/009514 EP2005009514W WO2006024545A1 WO 2006024545 A1 WO2006024545 A1 WO 2006024545A1 EP 2005009514 W EP2005009514 W EP 2005009514W WO 2006024545 A1 WO2006024545 A1 WO 2006024545A1
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flavone
acid
dihydroxy
coumarin
trihydroxy
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PCT/EP2005/009514
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Gerrigje Johanna Hageman
Harald Johan Joseph Moonen
Liesbeth Geraets
Aalt Bast
Emiel Frans Maria Wouters
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Stichting Voor De Technische Wetenschappen
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    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
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    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
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    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
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    • A61K31/33—Heterocyclic compounds
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    • A61K31/365—Lactones
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    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A61K31/37—Coumarins, e.g. psoralen
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4172—Imidazole-alkanecarboxylic acids, e.g. histidine
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
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    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines

Definitions

  • the invention relates generally to the field of inhibitors of the nuclear enzyme poly(adenosine 5'-diphospho-ribose) polymerase or "PARP" and to medical uses thereof.
  • PARP poly (ADP-ribose) polymerase, EC 2.4.2.30), also known as PARS (for poly(ADP- ribose) synthetase), or ADPRT (for NAD:protein (ADP-ribosyl) transferase (polymerising)), or pADPRT (for poly(ADP-ribose) transferase), is a major nuclear protein of 116 kDa. It is present in almost all eukaryotes, PARP protein is expressed at a high level in many tissues, most notably in the immune system, heart, brain and germ-line cells. Under normal physiological conditions, there is minimal PARP activity. However, DNA damage causes an immediate activation of PARP by up to 500-fold.
  • a number of inflammatory diseases such as bronchitis, lung emphysema, diabetes, rheumatism and chronic infections of the large intestine are characterized by an increase in oxidative stress, which causes damage to cells and tissues.
  • no anti-inflammatory compounds are available for use in preventing, treating an ⁇ /or alleviating chronic diseases or for use on a long-term, i.e. chronic, basis without the risk of inducing serious side-effects.
  • Inhibition of PARP-1 seems to reduce inflammatory processes.
  • the present inventors surprisingly found that a number of naturally occurring compounds inhibit the enzyme PARP-1.
  • NAD + -precursors as PARP-1 inhibitor compound.
  • the NAD + - precursors may be included to ensure optimal NAD + -status and energy metabolism in mitochondria.
  • over-activation of PARP-1 and the subsequent extensive turnover of the substrate NAD + puts a large demand on mitochondrial ATP-production. This may result in an energy crisis due to depletion of NAD + .
  • NAD + levels are reduced, the anaerobic glycolysis, mitochondrial respiration and ATP production are impaired.
  • Resynthesis of NAD + also requires ATP and poses a demand on mitochondrial energy production. Ultimately, these processes may lead to energy failure and necrosis, thus enhancing the oxidative stress and the inflammatory response.
  • the compounds of the invention have a weak to mild PARP-inhibitory activity and are therefore ideally suited for chronic use or for use by patients having specific diseases.
  • the compounds and compositions of the invention are suitable for counteracting the necrosis and inflammatory response of cells for specific groups of patients.
  • the compounds of the invention are described in detail below. It should be understood that many of these natural compounds may exist in plants as a derivative thereof, in the form of covalently bound sugar / oligosaccharide-derivatives, which can be isolated in that form from plants and used as the compounds of the invention, or used in that form in the compositions according to the invention.
  • derivatives of the compounds of the invention encompass, for instance, any glucose or raffinose or other mono- or oligosaccharide derivative of the compounds exemplified herein.
  • the present invention provides compounds of the formula (I) or pharmaceutically acceptable salts, hydrates, esters, solvates, prodrugs, derivatives, metabolites, stereoisomers thereof, for instance for use as anti-inflammatory agents, or for treating, preventing and/or alleviating a disease or disorder involving acute or chronic inflammation, diabetes, atherosclerosis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease (IBD), rheumatoid arthritis, ischemia and reperfusion damage, endotoxic or haemorrhagic shock, cancer, fibrosis, autoimmune diseases, and/or neuro ⁇ degenerative diseases wherein:
  • A represents the atoms necessary to form a fused 5- to 6-membered ring that is aromatic or nonaromatic, carbocyclic or heterocyclic; and wherein A and any heteroatom therein is unsubstituted or independently substituted with one of non-interfering hydroxyl, alkyl, double bonded oxygen, -OCH 3 , -NH-CO-CH 3 , or
  • R 3 , R 4 , R 5 , R 6 and R 7 are independently chosen from hydrogen, hydroxyl, alkyl, double bounded oxygen, -OCH 3 , or -NH-CO-CH 3 , -O-glucose or -O-raffinose;
  • X is -CHR 8 - or, -NR 9 -, where R 8 is hydrogen, hydroxyl, lower alkyl, -OCH 3 or -NH-CO-
  • CH 3 and R 9 is hydrogen, hydroxyl or lower alkyl
  • Y is -CHR 10 - or, -NR 11 -, where R 10 is hydrogen, hydroxyl, lower alkyl, -OCH 3 or -NH-
  • CO-CH 3 and R 11 is hydrogen, hydroxyl or lower alkyl
  • R 1 when present, is hydrogen, hydroxyl, amino, double bonded oxygen Or-OCH 3 ;
  • R 2 when present, is hydrogen, hydroxyl, amino, double bonded oxygen Or-OCH 3 .
  • these natural PARP-1 inhibitor compounds belong to the family of the xanthines and are generally represented by the formula (II) or by pharmaceutically acceptable salts, hydrates, esters, solvates, prodrugs, derivatives, metabolites or stereoisomers thereof, wherein:
  • R 1 and R 3 when present, are independently chosen from hydrogen and methyl;
  • R 2 , R 4 and R 7 when present, are independently chosen from hydrogen and double bonded oxygen;
  • R 5 when present, is either hydrogen or
  • R 6 when present, is either hydrogen, methyl or
  • the invention relates to the PARP-1 inhibitor compounds of formula (II), which are specifically mentioned in Table 1 , and to their use as a medicament, for the preparation of a medicament, as an anti-inflammatory agent, or as (an additive in) nutraceuticals, functional or medical food.
  • a compound selected from the group consisting of 1 ,7-dimethyluric acid, 1-methyluric acid, 1-methylxanthine, paraxanthine (1 ,7- dimethyl-xanthine), theobromine (3,7-dimethyl-xanthine), xanthine and xanthosine as a medicine, an anti-inflammatory agent, or as (an additive in) nutraceuticals or medical food.
  • these natural PARP-1 inhibitor compounds belong to the family of the coumarines and are generally represented by the formula (III) or by pharmaceutically acceptable salts, hydrates, esters, solvates, prodrugs, derivatives, metabolites or stereoisomers thereof, wherein: R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each independently chosen from hydrogen, hydroxyl, methyl, methoxy, COOH and -NH-CO-CH 3
  • the invention relates to the PARP-1 inhibitor compounds of formula (III) which are specifically mentioned in Table 2, and to their use as a medicament, for the preparation of a medicament, as an anti-inflammatory agent, or as (an additive in) functional or medical food or nutraceutical.
  • these compounds belong to the family of the flavonoids and are generally represented by the formula (IV)
  • R 1 or R 2 is phenyl, having one to five substituents which are independently chosen from hydrogen and hydroxyl, with the proviso that when R 1 or R 2 is not phenyl, it is hydrogen or hydroxyl; and R 3 , R 4 , R 5 and R 6 , when present, are independently chosen from hydrogen and hydroxyl.
  • solvate includes any combination which may be formed by a compound of this invention with a suitable inorganic solvent (e.g. hydrates) or organic solvent, such as but not limited to alcohols, ketones, esters and the like.
  • a "pro-drug” is considered a derivative of a (natural) compound that after ingestion and/or absorption is metabolized into its active form.
  • rutin - the glycosylated form of quercetin - can be hydrolyzed either by the intestinal microflora or by enzymes produced by intestinal cells or present in organs, into quercetin that is a PARP-inhibitor.
  • caffeine can also be considered a pro-drug.
  • pro-drug connotes pharmacologically acceptable derivatives such as esters, amides and phosphates, such that the resulting in vivo biotransformation product of the derivative is the active drug.
  • the reference by Goodman and Gilman The Pharmacological Basis of Therapeutics, 8th Ed, McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs", p 13-15) describing pro-drugs generally is hereby incorporated.
  • Pro-drugs of the compounds of the invention can be prepared by modifying functional groups present in said component in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent component.
  • Typical examples of pro-drugs are described for instance in WO 99/33795, WO 99/33815, WO 99/33793 and WO 99/33792, all of which are incorporated herein by reference.
  • Pro-drugs are characterized by increased bio-availability and are readily metabolized into the active inhibitors in vivo.
  • stereoisomeric form or "stereoisomere”, as used herein, defines all possible compounds made up of the same atoms bonded by the same sequence of bonds but having different three-dimensional structures which are not interchangeable, which the compounds of the present invention may possess.
  • chemical designation of a compound herein encompasses the mixture of all possible stereochemical)/ isomeric forms, which said compound may possess. Said mixture may contain all diastereomers and/or enantiomers of the basic molecular structure of said compound. All stereochemical ⁇ isomeric forms of the compounds of the invention either in pure form or in admixture with each other are intended to fall within the scope of the present invention.
  • substituted or “substituent” is used in the present invention, it is meant to indicate that one or more hydrogens on the atom indicated in the expression using “substituted” is replaced with a selection from the indicated group, provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a chemically stable compound, i.e. a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into a therapeutic agent.
  • compounds of the invention or “PARP-1 inhibitor compounds” or a similar term is used, it is meant to include the compounds of general formula I to VIII and any subgroup thereof.
  • the salts of the compounds according to the invention are those wherein the counter-ion is pharmaceutically or physiologically acceptable.
  • the invention relates to the PARP-1 inhibitor compounds of formula (IV) which are specifically mentioned in Table 3, and to their use as a medicament, for the preparation as a medicament, as an anti-inflammatory agent, or as (an additive in) nutraceuticals, functional or medical food.
  • apigenin (4',5,7-trihydroxy-flavone), baicalein (5,6,7-trihydroxy-flavone), chrysine (5,7-dihydroxy-flavone), daidzein (4',7-dihydroxyisoflavone), fisetin (5- deoxyquercetin; 3,3',4',7-tetrahydroxyflavone), galangin (3,5,7-trihydroxy-flavone), genistein (4',5,7-trihydroxy-isoflavone), gossypetin (3,5,7,8,3',4'-hexahydroxy-flavone), kaempferol (robigenin; 3,4',5,7-tetrahydroxy-flavone), luteolin (3',4',5,7-tetrahydroxy- flavone), morin (2',3,4',5,7-pentahydroxy-fla
  • these PARP-1 inhibitor compounds of formula (I) belong to the family of the anthocyanidins, and are generally represented by the formula (V)
  • R 1 and R 2 are independently chosen from hydrogen, hydroxy! and methoxy.
  • the invention relates to the PARP-1 inhibitor compounds of formula (V) which are specifically mentioned in Table 4, and to their use as a medicament, for the preparation of a medicament, as an anti-inflammatory agent, or as (an additive in) functional or medical food or a nutraceutical.
  • a compound selected from the group consisting of cyanidine, 4'O-methyl-delphinidin, delphinidin, malvidin, pelargonidin, peonidin and petunidin as a medicine, an anti-inflammatory agent, or as (an additive in) nutraceuticals or medical food.
  • the present invention further relates to compounds, belonging to the family of the lignans, generally represented by the formula (Vl), (VII) or (VIII)
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are independently chosen from hydrogen, hydroxyl or methoxy.
  • the invention relates to the compounds, belonging to the family of the lignans of formula (Vl), (VII) or (VIII) or to other lignans which are specifically mentioned in Table 5 and to their use as a medicament, for the preparation of a medicament, as an anti-inflammatory agent, or as (an additive in) nutraceuticals, functional or medical food.
  • the present invention further relates to the PARP-1 inhibitor compounds represented in Table 6 (polyphenols) for use, for instance, as a medicine, for the preparation of a medicament, as an anti-inflammatory agent, or as (an additive in) nutraceuticals, functional or medical food.
  • Table 6 polyphenols
  • the compounds allo-betulin, betulin, lupeol, nomilin and uvaol belong to the group of triterpenoid compounds (or saponins).
  • mixtures or (pharmaceutical) compositions of these natura) compounds of genera] formula (I) to (VI)I) are provided, which mixtures comprise low doses of each of the ingredients, and which, due to their additive or synergistic effect, are stronger and more effective than a comparable dose comprising only one of these compounds.
  • each PARP-1 inhibitor in a low dose in, for instance, nutraceuticals and food or food supplements, it is possible to avoid toxic effects which may occur much faster when only one inhibitor is used in the higher doses (or concentrations). Also differences between persons with respect to absorption, turn-over and decomposition of certain compounds need to be taken into account only to a lesser extend because a combination of inhibitors belonging to different chemical classes are used. For instance, it is found that a mixture comprising three PARP-inhibiting compounds from Table 3, each in a concentration of 3.33 ⁇ M, shows better PARP- inhibition related anti-inflammatory activity, than one of the individual compounds in a concentration of 10 ⁇ M.
  • the present invention also relates to the use of a composition as a medicament or for the preparation of a medicament, (an additive in) nutraceutical, medical or functional food characterized in that said composition comprises at least one, preferably at least two, more preferably at least three, four, five, six, seven, eight, nine or ten PARP-1 inhibitor compounds chosen from the group of compounds represented in any of Tables 1 to 6, preferably Table 1 , 2, 3, 4 or 6, and even more preferably, said at least one compound is chosen from the group of compounds consisting of adenosine, caffein (1 ,3,7- trimethylxanthine), 1 ,7-dimethyluric acid, hypoxanthine (6-oxypurine), inosine, 1- methyluric acid, 1-methylxanthine, paraxanthine (1 ,7-dimethyl-xanthine), theobromine (3,7-dimethyl-xanthine), theophylline (1 ,3-dimethylxanthine), xanthin
  • the present invention also relates to the use of a composition for the preparation of a medicament, (an additive in) nutraceutical, functional or medical food for treating, preventing and/or alleviating a disease or disorder involving chronic or acute inflammatory processes, characterized in that said composition comprises at least one, preferably at least two, even more preferably at least three or four, more preferably at least five, six, seven, eight, nine or ten poly (ADP-ribose) polymerase (PARP-1) inhibitor compounds chosen from the compounds represented in any of Tables 1 to 6, or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, derivative, metabolite or stereoisomer of any of said compounds.
  • PARP-1 poly (ADP-ribose) polymerase
  • the invention relates to the use of a pharmaceutical composition
  • a pharmaceutical composition comprising at least one, preferably two, more preferably at least three or four, even more preferably at least five, six, seven, eight, nine or ten PARP-1 inhibitor compounds as described above, wherein at least one compound is chosen from the group of compounds represented in any of Tables 1 to 6, or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, derivative, metabolite or stereoisomer of any of said compounds, and wherein at least another compound is an NAD+ precursor, preferably chosen from the group consisting of nicotinic acid (NIACIN); L-tryptophan; trigonelline derivatives; metabolites and pyrolysis products of trigonelline, such as for instance nicotinamide, 1-methylnicotinamide, 1-methyl-2-pyridone-5-carboxamide (2-PYR), 1- methyl-4-pyridone-5-carboxamide (4-PYR), and alkyl-pyri
  • said disease or disorder involving chronic or acute inflammatory processes is chosen from the group of diseases or disorders consisting of diabetes, atherosclerosis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease (IBD), rheumatoid arthritis, (chronic) asthma and heart failure, which diseases are characterized by chronic inflammation of tissues.
  • COPD chronic obstructive pulmonary disease
  • IBD inflammatory bowel disease
  • chronic rheumatoid arthritis
  • the invention relates to the use of any of the PARP-1 inhibitor compounds described herein to inhibit the formation of advanced glycation endproducts (AGEs) in patients with diabetes, and thereby enhance the glucose metabolism via oxidative pathways in these patients (e.g. the mechanism behind this action is that the activity of the enzyme glyceraldehyde-3-phosphate dehydrogenase is enhanced).
  • AGEs advanced glycation endproducts
  • the invention also relates to the use as described above for preventing, treating or alleviating acute inflammation, such as, for instance, acute inflammation due to or as a result of ischemia or reperfusion damage, or due to endotoxic or haemorrhagic shock .
  • the present invention relates to the use of a composition for the preparation of a medicament, (an additive in) nutraceutical, functional or medical food for treating, preventing and/or alleviating cancer, characterized in that said composition comprises at least one or two, preferably at least three or four, more preferably at least five, six, seven, eight, nine or ten PARP-1 inhibitor compounds chosen from the compounds represented in any of Tables 1 , 2, 3, 4, 5 and 6, or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, derivative, metabolite or stereoisomer of any of said compounds.
  • the invention relates to the use of a pharmaceutical composition
  • a pharmaceutical composition comprising at least one or two, preferably at least three or four, more preferably at least five, six, seven, eight, nine or ten PARP-1 inhibitor compounds as described above, wherein at least one compound is chosen from the group of compounds represented in any of Tables 1 , 2, 3, 4, 5 and 6, or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, derivative, metabolite or stereoisomer of any of said compounds, and wherein at least another compound is an NAD + precursor, preferably chosen from the group consisting of nicotinic acid (NIACIN); L-tryptophan; trigonelline derivatives; metabolites and pyrolysis products of trigonelline, such as for instance nicotinamide, 1 -methylnicotinamide, 1-methyl-2-pyridone-5-carboxamide (2- PYR), 1-methyl-4-pyridone-5-carboxamide (4-PYR), and alkyl
  • the present invention relates to the use of a composition for the preparation of a medicament, (an additive in) nutraceutical, functional or medical food for treating, preventing and/or alleviating fibrosis, characterized in that said composition comprises at least one or two, preferably at least three or four, more preferably at least five, six, seven, eight, nine or ten PARP-1 inhibitor compounds chosen from the compounds represented in any of Tables 1 , 2, 3, 4, 5 and 6, or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, derivative, metabolite or stereoisomer of any of said compounds.
  • the invention relates to the use of a pharmaceutical composition
  • a pharmaceutical composition comprising at least one or two, preferably at least three or four, more preferably at least five, six, seven, eight, nine or ten PARP-1 inhibitor compounds as described above, wherein at least one compound is chosen from the group of compounds represented in any of Tables 1 , 2, 3, 4, 5 and 6, or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, derivative, metabolite or stereoisomer of any of said compounds, and wherein at least another compound is an NAD + precursor, preferably chosen from the group consisting of nicotinic acid (NIACIN); L-tryptophan; trigonelline derivatives; metabolites and pyrolysis products of trigonelline, such as for instance nicotinamide, 1-methylnicotinamide, 1-methyl-2-pyridone-5-carboxamide (2- PYR), 1-methyl-4-pyridone-5-carboxamide (4-PYR), and alkyl-pyr
  • the present invention relates to the use of a composition for the preparation of a medicament, (an additive in) nutraceutical, functional or medical food for treating, preventing and/or alleviating autoimmune diseases, preferably autoimmune diseases that cause damage to various organs (e.g. kidneys, lungs, heart, intestines) and tissues (e.g.
  • composition comprises at least one or two, preferably at least three or four, more preferably at least five, six, seven, eight, nine or ten PARP-1 inhibitor compounds chosen from the compounds represented in any of Tables 1 , 2, 3, 4, 5 and 6, or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, derivative, metabolite or stereoisomer of any of said compounds.
  • the invention relates to the use of a pharmaceutical composition
  • a pharmaceutical composition comprising at least one or two, preferably at least three or four, more preferably at least five, six, seven, eight, nine or ten PARP-1 inhibitor compounds as described above, wherein at least one compound is chosen from the group of compounds represented in any of Tables 1 , 2, 3, 4, 5 and 6, or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, derivative, metabolite or stereoisomer of any of said compounds, and wherein at least another compound is an NAD + precursor, preferably chosen from the group consisting of nicotinic acid (NIACIN); L-tryptophan; trigonelline derivatives; metabolites and pyrolysis products of trigonelline, such as for instance nicotinamide, 1-methylnicotinamide, 1-methyl-2-pyridone-5-carboxamide (2- PYR), 1-methyl-4-pyridone-5-carboxamide (4-PYR), and alkyl-pyr
  • the present invention relates to the use of a composition for the preparation of a medicament, (an additive in) nutraceutical, functional or medical food for treating, preventing and/or alleviating neurodegenerative diseases, characterized in that said composition comprises at least one or two, preferably at least three or four, more preferably at least five, six, seven, eight, nine or ten PARP-1 inhibitor compounds chosen from the compounds represented in any of Tables 1 , 2, 3, 4, 5 and 6, or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, derivative, metabolite or stereoisomer of any of said compounds.
  • the invention relates to the use of a pharmaceutical composition
  • a pharmaceutical composition comprising at least one or two, preferably at least three or four, more preferably at least five, six, seven, eight, nine or ten PARP-1 inhibitor compounds as described above, wherein at least one compound is chosen from the group of compounds represented in any of Tables 1 , 2, 3, 4, 5 and 6, or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, derivative, metabolite or stereoisomer of any of said compounds, and wherein at least another compound is an NAD + precursor, preferably chosen from the group consisting of nicotinic acid (NIACIN); L-tryptophan; trigonelline derivatives; metabolites and pyrolysis products of trigonelline, such as for instance nicotinamide, 1-methylnicotinamide, 1-methyl-2-pyridone-5-carboxamide (2- PYR), 1-methyl-4-pyridone-5-carboxamide (4-PYR), and alkyl-pyr
  • said neurodegenerative diseases is Alzheimer's disease, Parkinson's disease or amyotrophic lateral sclerosis (ALS).
  • the invention relates to the uses of compositions as described above, wherein the inclusion of an NAD + precursor is optional.
  • the invention relates to any of the uses as described above wherein said PARP-1 inhibitor compounds is chosen from the group consisting of adenosine, caffein (1 ,3,7-trimethylxanthine), 1 ,7-dimethyluric acid, hypoxanthine (6- oxypurine), inosine, 1-methyluric acid, 1 -methylxanthine, paraxanthine (1 ,7-dimethyl- xanthine), theobromine (3,7-dimethyl-xanthine), theophylline (1 ,3-dimethyl-xanthine), xanthine, xanthosine, 3-acetamido-coumarin, 6-acetamido-coumarin, auraptene, couma ⁇ n, coumarin-3-carboxylic acid, daphnetin (7,8-dihydroxy-coumarin), 5,7-dihydroxy- 4-methylcoumarin, 6,7-dihydroxy-4-methylcoumarin, esculetin
  • the present invention particularly contemplates the use of a composition for the preparation of a medicament, medical food or nutraceutical, or an additive therefor, for treating, preventing, and/or alleviating a disease or disorder as described herein, wherein said composition comprises at least two compounds, wherein a first compound is a poly (ADP-ribose) polymerase (PARP-1) inhibitor compound as described herein, and wherein a second compound is an NAD + precursor as described herein.
  • PARP-1 poly (ADP-ribose) polymerase
  • PARP-1 poly (ADP-ribose) polymerase
  • the invention relates to any of the uses described above wherein said composition comprises one of the combinations of compounds as represented in Table 7 or 8.
  • said composition comprises a xanthine compound chosen from Table 1 , a coumarine compound chosen from Table 2 and, optionally, an NAD + precursor, preferably chosen from the group consisting of nicotinic acid (NIACIN); L-tryptophan; trigonelline derivatives; metabolites and pyrolysis products of trigonelline, such as for instance nicotinamide, 1-methylnicotinamide, 1-methyl-2-pyridone-5-carboxamide (2- PYR), 1-methyl-4-pyridone-5-carboxamide (4-PYR), and alkyl-pyridiniums, such as 1- methylpyridinium, 1 ,4-dimethyl-pyridinium; or a pharmaceutical
  • the invention encompasses also the use of a compound chosen from the list consisting of adenosine, caffein (1,3,7-trimethylxanthine), hypoxanthine (6-oxypurine), inosine, theophylline (1 ,3-dimethyl-xanthine), esculetin (6,7-dihydroxycoumarin), 4-hydroxy- coumarin, flavone (2-phenyl-chromone), quercetin (3,3',4',5,7-pentahydroxy-flavone), caffeic acid, catechine, chlorogenic acid, curcumin, ellagic acid, folic acid (vitamin M), 18 ⁇ - glycyrrhetinic acid, L-homocarnosine, isonicotinamide, nicotinamide (niacinamide/vitamin B 3 ), nicotinic acid (niacin/vitamin B 3 ) and purpurin (an anthraquinoid), or a pharmaceutical
  • the pharmaceutically acceptable salts of the compounds according to the invention include the conventional non-toxic salts or the quaternary ammonium salts which are formed, e.g., from inorganic or organic acids or bases.
  • acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tos
  • Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D- glucamine, and salts with amino acids such a sarginine, lysine, and so forth.
  • the basic nitrogen-containing groups may be quatemized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl-bromides and others.
  • Other pharmaceutically acceptable salts include the sulfate salt ethanolate and sulfate salts.
  • the compounds and compositions described herein can be used to prevent or treat the onset or progression of any disease or condition related to PARP activity in mammals, especially humans. Such conditions include acute and chronic inflammation, endotoxic shock, diabetes, arthritis, cardiac ischemia, retinal ischemia, skin aging, acute stroke, chronic and acute pain, hemorrhagic shock, and others.
  • the compounds and compositions described herein may be used for inhibiting an inflammatory response by prevention of necrosis.
  • a patient following the symptoms of a stroke, a patient can be administered one or more compounds described herein to prevent or minimize damage to the brain.
  • the compounds and compositions may be used for the prevention and/or the therapy of ischaemia and reperfusion damage.
  • inventions include the use of the compounds or compositions described herein for the inhibition of inflammatory processes mediated by NF- ⁇ B or for the inhibition of stress-response processes mediated by AP-1.
  • the invention also relates to the use of the compounds or compositions of the invention for inhibition of NF-/d3-mediated inflammatory processes in chronic inflammatory diseases (for instance, but not limited to diabetes, atherosclerosis, chronic obstructive pulmonary disease (COPD), inflammatory bowel diseases (IBD), rheumatoid arthritis), or for the prevention of bone resorption in postmenopausal osteoporosis and due to implant particles/debris.
  • chronic inflammatory diseases for instance, but not limited to diabetes, atherosclerosis, chronic obstructive pulmonary disease (COPD), inflammatory bowel diseases (IBD), rheumatoid arthritis
  • chronic inflammatory diseases for instance, but not limited to diabetes, atherosclerosis, chronic obstructive pulmonary disease (COPD), inflammatory bowel diseases
  • the invention also relates to the use of the compounds or compositions described herein for preventing, treating and/or alleviating COPD to reduce the consequent muscle weakness and/or muscle breakdown effects. Still other embodiments of the invention relate to the use of the compounds or compositions described herein for preventing apoptosis in non-cancerous cells.
  • the compounds and compositions of the invention are also useful for prevention of skin-aging, especially increased break-down of collagen.
  • Other PARP related conditions or diseases treatable by the compounds or compositions described herein include traumatic injury to the central nervous system, such as brain and spinal cord injuries, and the neuronal degradation associated with traumatic injury to the central nervous system.
  • Related conditions and diseases treatable by methods of the present invention include vascular strokes, cardiac ischemia, cerebral ischemia, cerebrovascular disorders such as multiple sclerosis, and neurodegenerative diseases such as Alzheimer's, Huntington's, and Parkinson's diseases.
  • Patients with symptoms of Alzheimer's, Huntington's, or Parkinson's disease can be treated with compounds of the present invention to halt the progression of the disease or alleviate symptoms.
  • PARP inhibitors may also be used to treat patients suffering from cancer. For instance, cancer patients can be administered the present compounds in order to augment the anti-tumour effects of chemotherapy.
  • preventing, treating and/or alleviating any of the diseases mentioned herein is accomplished by the administration of a therapeutically effective amount of the compounds or compositions of the invention are administered to a patient in need thereof.
  • patient relates to mammals, especially humans.
  • the invention thus also relates to a method for preventing, treating and/or alleviating an inflammatory process in a patient, as well as methods for preventing, treating and/or alleviating cancer, fibrosis, autoimmune diseases or neurodegenerative diseases in a patient, comprising administering to a patient a therapeutically effective amount of a compound chosen from the list consisting of adenosine, caffein (1 ,3,7-trimethylxanthine), 1 ,7-dimethyluric acid, hypoxanthine (6- oxypurine), inosine, 1-methyluric acid, 1-methylxanthine, paraxanthine (1 ,7-dimethyl- xanthine), theobromine (3,7-dimethyl-xanthine), theophylline (1 ,3-dimethylxanthine), xanthine, xanthosine, 3-acetamido-coumarin, 6-acetamido-coumarin, auraptene, coumarin,
  • the method for preventing, treating and/or alleviating inflammatory process, cancer, fibrosis, autoimmune diseases or neurodegenerative diseases comprises administering to a patient a therapeutically effective amount of NAD + precursor, preferably chosen from the group consisting of nicotinic acid (NIACIN); L-tryptophan; trigonelline derivatives; metabolites and pyrolysis products of trigonelline, such as for instance nicotinamide, 1-methylnicotinamide, 1- methyl-2-pyridone-5-carboxamide (2-PYR), 1-methyl-4-pyridone-5-carboxamide (4-PYR), and alkyl-pyridiniums, such as 1-methylpyridinium, 1 ,4-dimethyl-pyridinium; or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, derivative, metabolite or stereoisomer of any of said NAD + precursors.
  • NAD + precursor preferably chosen from the group consisting of nicot
  • the present invention relates to a medicament, (an additive in) a nutraceutical or a medical food for treating, preventing and/or alleviating a disease or disorder involving chronic or acute inflammatory processes
  • a first compound is a poly (ADP-ribose) polymerase (PARP-1 ) inhibitor compound chosen from the group consisting of caffein (1 ,3,7-trimethylxanthine), 1 ,7-dimethyluric acid, 1- methyluric acid, 1-methylxanthine, paraxanthine (1 ,7-dimethyl-xanthine), theobromine (3,7-dimethyl-xanthine), theophylline (1,3-dimethylxanthine), 3-acetamido-coumarin, 6- acetamido-coumarin, auraptene, coumarin, coumarin-3-carboxylic acid, daphnetin (7,8- dihydroxy-coumarin), 5,7-dihydroxy-4-
  • PARP-1 poly (ADP
  • the PARP-1 inhibitor compounds of the present invention will normally be formulated into a pharmaceutical composition in accordance with pharmaceutical practice.
  • PARP-1 inhibitors may be administered by any route that drugs are conventionally administered.
  • routes of administration include intraperitoneal, intravenous, intramuscular, subcutaneous, intrathecal, intratracheal, intraventricular, oral, buccal, rectal, parenteral, intranasal, transdermal, intradermal or by inhalation. Administration may be systemic or localized.
  • compositions described herein may be administered in pure form, combined with other active ingredients, or combined with pharmaceutically acceptable nontoxic excipients or carriers.
  • Oral compositions will generally include an inert diluent carrier or an edible carrier.
  • Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • Tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a dispersing agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a dispersing agent such as alginic acid, Primogel, or corn starch
  • a lubricant such as magnesium stearate
  • a glidant such as colloidal silicon dioxide
  • a sweetening agent such as sucrose or
  • dosage unit forms can contain various other materials that modify the physical form of the dosage unit, for example, coatings of sugar, shellac, or enteric agents.
  • a syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes, colorings, and flavorings.
  • sucrose as a sweetening agent
  • certain preservatives dyes, colorings, and flavorings.
  • the carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • Alternative preparations for administration include sterile aqueous or nonaqueous solutions, suspensions, and emulsions.
  • nonaqueous solvents are dimethylsulfoxide, alcohols, propylene glycol, polyethylene glycol, vegetable oils such as olive oil and injectable organic esters such as ethyl oleate.
  • Aqueous carriers include mixtures of alcohols and water, buffered media, and saline.
  • Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers, such as those based on Ringer's dextrose, and the like. Preservatives and other additives may also be present such as, for example, antimicrobials, anti-oxidants, chelating agents, inert gases, and the like.
  • Preferred methods of administration of the present compounds to mammals include intraperitoneal injection, intramuscular injection, and intravenous infusion.
  • Various liquid formulations are possible for these delivery methods, including saline, alcohol, DMSO, and water
  • the term "therapeutically effective amount” is meant to refer to an amount of a compound or composition of the present invention that will elicit a desired therapeutic or prophylactic effect or response when administered according to the desired treatment regimen.
  • the PARP-inhibiting compounds or compositions including nutraceuticals, functional and medical foods of the invention are administered to a subject, e.g. a patient in such a dose that a plasma concentration between about 1 nM and 10 mM of the active ingredients, including metabolites, is obtained.
  • said plasma concentration is between 0.1 and 50 ⁇ M or between 0.5 and 40 ⁇ M, more preferably, said plasma concentration is between 1 and 30 ⁇ M, or between 2 and 20 ⁇ M or between 5 and 15 ⁇ M or about 10 ⁇ M per compound. It will be appreciated by the person skilled in the art that plasma concentrations above 100 ⁇ M per compound toxic effects may occur for some of these compounds in normal human cells.
  • the NAD + precursors in the compositions according to the invention are administered to a subject, e.g. a patient in such a dose that a plasma concentration between about 1 nM and 100 mM of the active ingredients, including metabolites, is obtained.
  • a plasma concentration between about 1 nM and 100 mM of the active ingredients, including metabolites, is obtained.
  • said plasma concentration is between 10 nM and 10 mM or between
  • said plasma concentration is between 1 ⁇ M and 100 ⁇ M, or between 2 and 50 ⁇ M or between 5 and 25 ⁇ M or about 10 ⁇ M per compound.
  • whole blood (containing blood cells and plasma) concentrations are in the millimolar range.
  • Plasma concentrations above 50 ⁇ M of compounds may exert toxic effects in normal human cells.
  • the compounds or composition is provided in a unit dosage form, for example a tablet, capsule or metered aerosol dose, so that a single dose is administered to the subject, e.g. a patient.
  • Each dosage unit for oral administration contains suitably from about 0.1 mg to about 60 mg/Kg, preferably from about 0.3 mg to about 30 mg/Kg and even more preferably from about 0.6 mg to about 6.25 mg/Kg of a compound or a pharmaceutically acceptable salt thereof, all measured as the free base per weight expressed in Kg of the subject, e.g. a patient, receiving said compound.
  • Each dosage unit for parenteral administration contains suitably from 0.1 mg to 60 mg/Kg, of the compound or a pharmaceutically acceptable salt thereof.
  • a dose unit may contain about 5 to 1000 mg, or 50 to 500 mg, or 100 to 250 mg of an active ingredient.
  • Each dosage unit for intranasal administration contains suitably 1-400 ⁇ g and preferably 10 to 200 ⁇ g per activation.
  • a dry powder inhalation dose could contain 1-1000 micrograms per dose unit.
  • a topical formulation contains suitably 0.001 to 5.0% of a present compound.
  • the man skilled in the art knows how to define or calculate the actual dose to be administered to a patient.
  • the dosage unit for oral administration of the NAD + precursor contains between about 0.1 mg to about 60 mg/Kg, preferably from about 0.3 mg to 30 mg/Kg, even more preferably from about 0.6 mg to about 6.25 mg/Kg, more preferably from about 0.9 mg to about 3.6 mg/Kg and even more preferably from about 1.2 mg to about 2.4 mg/Kg.
  • a dose unit may contain about 0.5 to 500 mg, or about 1 to 250, or about 5 to 200 mg, or about 10 to 100 mg, or 25 to 75 mg, or about 50 mg of an active ingredient.
  • the active ingredient may be administered from 1 to 6 times a day, sufficient to exhibit the desired activity. These daily doses can be given as a single dose once daily, or can be given as two or more smaller doses at the same or different times of the day which in total give the specified daily dose. Preferably, the active ingredient is administered once or twice a day. It is contemplated that both active agents would be administered at the same time, or very close in time. Alternatively, one compound could be taken in the morning and one later in the day. Or in another scenario, one compound could be taken twice daily and the other once daily, either at the same time as one of the twice-a-day dosing occurred, or separately. Preferably both compounds would be taken together at the same time and be administered as an admixture.
  • the second compound is administered simultaneously with, separate from or sequential to said first compound.
  • the daily maintenance dose can be given for a period clinically desirable in the patient, for example from 1 day up to several years (e.g. for the mammal's entire remaining life); for example from about (2 or 3 or 5 days, 1 or 2 weeks, or 1 month) upwards and/or for example up to about (5 years, 1 year, 6 months, 1 month, 1 week, or 3 or 5 days).
  • Administration of the daily maintenance dose for about 3 to about 5 days or for about 1 week to about 1 year is typical.
  • Other constituents of the liquid formulations may include preservatives, inorganic salts, acids, bases, buffers, nutrients, vitamins, or other pharmaceuticals such as analgesics or additional PARP inhibitors.
  • Compounds of the present invention also may take the form of a pharmacologically acceptable salt, hydrate, solvate, or metabolite.
  • Pharmacologically acceptable salts include basic salts of inorganic and organic acids, including but not limited to hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, nitric acid, methanesulphonic acid, ethanesulfonic acid, p-toluenesulfonic acid, naphtalenesulfonic acid, malic acid, acetic acid, oxalic acid, tartaric acid, citric acid, lactic acid, fumaric acid, succinic acid, maleic acid, salicylic acid, benzoic acid, phenylacetic acid, mandelic acid and the like.
  • acids of the invention include an acidic function, such as a carboxy group
  • suitable pharmaceutically acceptable cation pairs for the carboxy group are well known to those skilled in the art and include alkaline, alkaline earth, ammonium, quaternary ammonium cations and the like.
  • compositions of the invention may be used as nutraceuticals, functional or medical food, or as additives in said nutraceuticals, functional or medical food
  • the invention also relates to (additives for) nutraceuticals, functional or medical food comprising at least one or two, preferably at least three or four, more preferably at least five, six, seven, eight, nine or ten PARP-1 inhibitor compounds identified in the present invention, i.e. any of the compounds represented in Tables 1 , 2, 3, 4, 5 and 6, or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, derivative, metabolite or stereoisomer of any of said compounds.
  • the (additives in) nutraceuticals, functional or medical food according to the invention comprise a therapeutically effective amount of NAD + precursor, preferably chosen from the group consisting of nicotinic acid (NIACIN); L-tryptophan; trigonelline derivatives; metabolites and pyrolysis products of trigonelline, such as for instance nicotinamide, 1-methylnicotinamide, 1-methyl-2-pyridone-5-carboxamide (2-PYR), 1- methyl-4-pyridone-5-carboxamide (4-PYR), and alkyl-pyridiniums, such as 1-methyl- pyridinium, 1 ,4-dimethyl-pyridinium; or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, derivative, metabolite or stereoisomer of any of said NAD + precursors.
  • NAD + precursor preferably chosen from the group consisting of nicotinic acid (NIACIN); L-tryptophan;
  • nutraceutical denotes usefulness in both the nutritional and pharmaceutical field of application. Therefore, the novel nutraceutical composition can be used as a supplement to food and beverages, and as pharmaceutical formulation for enteral or parenteral application, which may be solid formulations such as capsules or tablets, or liquid formulations such as solutions or suspensions as described above. As will be evident from the foregoing, the term nutraceutical composition also comprises food and beverages containing PARP-1 inhibitors as well as supplement compositions containing both active ingredients.
  • the nutraceutical of the present invention contains PARP-1 inhibitors in an amount sufficient to administer to a subject a dosage as specified above.
  • Another embodiment provides a food or beverage, preferably fit for human consumption, which is comprised of a nutraceutical and a flavoring agent, wherein the nutraceutical is comprised of an extract from an agricultural product.
  • Nutraceuticals whether in the form of a liquid extract or dry composition, are edible and may be eaten directly by humans, but are preferably provided to humans in the form of additives or nutritional supplements e.g., in the form of tablets of the kind sold in health food stores, or as ingredients in edible solids, more preferably processed food products such as cereals, breads, tofu, cookies, ice cream, cakes, potato chips, pretzels, cheese, etc., and in drinkable liquids e.g., beverages such as milk, soda, sports drinks, and fruit juices.
  • a method is provided for enhancing the nutritional value of a food or beverage by intermixing the food or beverage with a nutraceutical in an amount that is effective to enhance the nutritional value of the food or beverage.
  • Another embodiment provides a method for enhancing the nutritional value of a food or beverage which comprises intermixing a food or a beverage with a nutraceutical to produce a nutritionally-enhanced food or beverage, wherein the nutraceutical is intermixed in an amount effective to enhance the nutritional value of the food or beverage, wherein the nutraceutical is comprised of an extract from a crop comprising the PARP-1 inhibitors of the present invention, and wherein the nutritionally-enhanced food or beverage may further comprise a flavoring agent.
  • Preferred flavoring agents include sweeteners such as sugar, corn syrup, fructose, dextrose, maltodextrose, cyclamates, saccharin, phenyl ⁇ alanine, xylitol, sorbitol, maltitol, and herbal sweeteners e.g., Stevia.
  • the nutraceuticals described herein are intended for human consumption and thus the processes for obtaining them are preferably conducted in accordance with Good Manufacturing Practices (GMP) and any applicable government regulations governing such processes. Especially preferred processes utilize only naturally derived solvents.
  • the nutraceuticals described herein preferably contain relatively high levels of health- enhancing substances Nutraceuticals may be intermixed with one another to increase their health-enhancing effects.
  • Medical foods are not meant to be used by the general public and are not available in stores or supermarkets. Medical foods are not those foods included within a healthy diet to decrease the risk of disease, such as reduced-fat foods or low-sodium foods, nor are they weight loss products.
  • a physician prescribes a medical food when a patient has special nutrient needs in order to manage a disease or health condition, and the patient is under the physician's ongoing care. The label must clearly state that the product is intended to be used to manage a specific medical disorder or condition.
  • An example of a medical food is nutritionally diverse medical food designed to provide targeted nutritional support for patients with chronic inflammatory conditions. Active compounds of this product are for instance one or more of the compounds described herein. Functional foods may encompass those foods included within a healthy diet to decrease the risk of disease, such as reduced-fat foods or low- sodium foods, or weight loss products.
  • Medical foods are especially contemplated for improving recovery after a hemorrhagic shock.
  • Patients in need of surgery may be treated daily with the medical foods of the invention, in order to enhance recovery and reduction of time spent in the hospital.
  • the patients may be treated before and/or after surgery with the medical foods of the invention.
  • the present invention contemplates a food or beverage comprising a nutrace ⁇ t ⁇ ca ⁇ according to the invention.
  • composition encompasses plant extracts comprising at least one and preferably at least two of the PARP-1 inhibitor compounds of the present invention.
  • pharmaceutical composition encompasses plant extracts comprising at least one and preferably at least two of the PARP-1 inhibitor compounds of the present invention.
  • plant extracts relates to an extract of a plant, plant seeds, roots, sprouts or plant cells comprising at least one and preferably at least two PARP-1 inhibitor compounds as described herein.
  • An extract of a plant may be obtained by withdrawing by expression, distillation, or any other mechanical or chemical process, whereby the activity of the PARP-1 inhibitor compounds remains essentially intact.
  • an extract relates to a concentrated preparation of a vegetable drug obtained by removing the active constituents, i.e. the PARP-1 inhibitor compounds, therefrom with a suitable menstruum, evaporating all or nearly all the solvent and adjusting the residual mass or powder to a prescribed standard.
  • extracts are prepared in three forms, semiliquid or of syrupy consistency, pilular or solid and as dry powder.
  • the extract is comprised of a substance selected from the group consisting of carbohydrate, sugar, fat, protein, amino acid, vitamin, anti-oxidant, polyphenol, caffeic acid, ferulic acid, and chlorogenic acid, more preferably an anti-oxidant.
  • the flavoring agent is a sweetener.
  • the solvent may be comprised of a liquid selected from the group consisting of water, an aqueous salt solution, ethanol, isopropanol, n-butanol, glycerol, carbon dioxide, acetone, methyl ethyl ketone, ethyl acetate, propyl acetate, butyl acetate, and mixtures thereof.
  • the plant extracts according to the invention may be used for the preparation of (an additive in) a functional or medical food or nutraceutical for treating, preventing and/or alleviating a disease as defined herein, e.g. chronic or acute inflammatory processes, diabetes, atherosclerosis, chronic obstructive pulmonary disease, IBD, rheumatoid arthritis, ischemia and reperfusion damage, endotoxic or haemorrhagic shock, cancer, fibrosis, autoimmune disease or neurodegenerative disease.
  • a disease e.g. chronic or acute inflammatory processes, diabetes, atherosclerosis, chronic obstructive pulmonary disease, IBD, rheumatoid arthritis, ischemia and reperfusion damage, endotoxic or haemorrhagic shock, cancer, fibrosis, autoimmune disease or neurodegenerative disease.
  • a disease e.g. chronic or acute inflammatory processes, diabetes, atherosclerosis, chronic obstructive pulmonary disease, IBD, rhe
  • Table 9 represents results of PARP-activity measurements. Therefore, pure PARP-1 was incubated with the substrate NAD + and the PARP-inhibitors to be tested. The names of test-compounds are depicted in the table. In each of the experiments, 3-aminobenzamine (3-AB) was used as a control. 3-aminobenzamide is a frequently used synthetic PARP-1 inhibitor. Each compound was tested at least 3 times and most were tested 6 times. The data presented are the mean of 3-6 replications. In Table 9, the % inhibition after incubation of the respective PARP-inhibitor test- compounds (at a concentration of 100 ⁇ M, or indicated if different) with pure PARP-1 is designated.
  • the activity of the PARP-1 inhibitor test compounds were measured in a PARP inhibition ELISA (ELISA) and in a cell culture NAD+ assay (Cell assay).
  • ELISA PARP inhibition ELISA
  • Cell assay cell culture NAD+ assay
  • Patients suffering from chronic inflammatory diseases such as COPD are treated with specific nutritional supplements or preparations that contain a combination of a NAD + - precursor and one or more of the PARP-inhibiting compounds listed in Tables 1-4 and 6.
  • mice are repeatedly challenged with LPS (E coli, serotype 055: B5: Sigma Chemical Co.) twice a week for a period of 12 wk by intratracheal instillation to induce a chronic pulmonary inflammation.
  • Sham mice are instilled intratracheally with LPS-free sterile 0.9% NaCI, whereas control mice receive no treatment.
  • Intratracheal instillation is performed by a nonsurgical technique.
  • mice are anesthetized by intraperitoneal injection of xylazin/ketamin. A volume of 50 ⁇ l is instilled intratracheally via a canule, followed by 0.1 ml of air.
  • mice After intratracheal treatment, the mice are kept in an upright position for 10 min to allow sufficient spreading of the fluid throughout the lungs. Mice are killed 1 wk after the final intratracheal instillation.
  • Saline group (n 10): intratracheal instillation of 50 ⁇ l sterile saline; mice are killed 1 wk after the final intratracheal instillation.
  • Control group (n 5): age-matched control mice.
  • Single PARP-inhibitors or combinations of several natural PARP-inhibitors is administered to a group of 10 mice. For each group, a group of 5 pair-fed mice is formed that receives the standard lab chow (SRM-A; Hope Farms, Woerden, the Netherlands) and are treated with LPS as described above.
  • Morin (M), fisetin (F), theobromine (T), 1 ,7-dimethylxanthine (X) and delphinidin (C) are added to standard lab chow ensuring an intake of PARP- inhibiting compounds by the mice in the range of 5-50 mg/kg/day (for each compound) with plasma concentrations between 1-10 ⁇ M.
  • 5 mice are sham-treated with LPS-free saline and 5 mice are treated with LPS as described above.
  • Example 3 Amelioration of vascular dysfunction in diabetes Patients with diabetes experience problems with vascular function that cause a dysfunction of important organs and tissues (heart, kidneys, retina, neurons) and problems with blood flow through peripheral tissues in toes and feet that can lead to loss of these tissues (amputation of toes or a foot).
  • Human whole blood was acquired by venapunction in blood tubes containing EDTA or heparin. Immediately hereafter, or after storage at 4 0 C or 37 0 C for a maximum of 8 hours, the blood was aliquoted into cell culture wells and diluted 4 times with culture medium.
  • the diluted blood was then pre-incubated for 30 min at 37 0 C with potential PARP-1 inhibiting compounds or mixtures thereof (see Tables 1-4 and 6). Subsequently, LPS was added (final concentration between 1 ng/ml and 1 ⁇ g/ml) and the blood was incubated for 16 or 24 hours at 37 0 C.
  • cytokine levels e.g. IL-6
  • Figure 1 is a summary of the anti-inflammatory activity of different PARP-1 inhibitors and combinations of PARP-1 inhibitors in human blood from a patient with diabetes.
  • diabetes patients daily receive specific nutritional supplements or preparations that contain a combination of a NAD + -precursor and one or more of the PARP-inhibiting compounds listed in Tables 1-4 and 6.
  • mice are treated with streptozotocin (240 mg/kg IP) or vehicle (citrate buffer). Blood glucose is monitored weekly; hyperglycemia is defined as nonfasting blood glucose level >11 mmol/l. When hyperglycemia is established, mice are fed the expermimental diet as indicated below.
  • the effect of a combination of PARP-inhibitors is studied as follows: Each compound or combination of compounds is administered to a group of 10 mice. Of each diet group, 5 mice are sham-treated with vehicle and these serve as controls for potential side effects of the administered natural PARP-inhibitors and 5 mice are treated with streptozotocin.
  • mice For each experimental diet group, a group of 5 pair-fed mice is formed that receive the standard lab chow (SRM-A; Hope Farms, Woerden, the Netherlands) and are also treated with streptozotocin as described above. Morin (M), fisetin (F), 1 ,7-dimethylxantine (X), theobromine (T), delphinidin (D) are added to standard lab chow ensuring an intake of each compound in the range of 5-50 mg/kg/day with plasma concentrations of free plus conjugated compounds in the range of 1-10 ⁇ M.
  • SRM-A Standard lab chow
  • Morin (M) fisetin
  • X 1 ,7-dimethylxantine
  • T theobromine
  • D delphinidin
  • mice After 4 weeks on the experimental diet, mice are killed, blood collected and aorta is excised as described by Knaapen et al. (Knaapen et al. (2001) "Ambient particulate matter induces relaxation of rat aortic rings in vitro.” Hum-Exp-Toxicol. 20(5): 259-65). Aortic rings of approx. 2 mm are transferred into organ baths and vascular function is determined by measuring relaxation with acetylcholine (Ach; 1x10 '6 mol/l) after precontracting with phenylephrine (PE; 3x10 "6 mol/l).
  • Ach acetylcholine
  • PE phenylephrine
  • mice of an age of 5 wk (10/group) are fed a standard lab chow (SRM-A; Hope Farms, Woerden, the Netherlands) for a period of 10 weeks to which Morin (M), fisetin (F), theobromine (T), 1 ,7-dimethylxantine (X), delphinidin (D) are added in such amounts that the intake of the mice is in the range of 5-50 mg/kg/day with plasma concentrations of free plus conjugated compounds in the range of 1-10 ⁇ M.
  • SRM-A Standard lab chow
  • mice receives the standard diet without additions.
  • Wild-type mice (10/group) receive the experimental diets and serve as controls for potential side effects.
  • mice After 12 weeks, mice are killed and the arterial tree collected as described by Curfs et al. (2004).
  • the number of atherosclerotic lesions per aortic arch and mean aortic plaque size, infiltrations of lymphocytes and macrophages in atherosclerotic plaques are determined as described by Curfs et al. (2004).
  • lmmunehistochemical evaluation of PARP-activation in endothelial cells was done as described elsewhere (Hageman et al. (2003) "Systemic poly(ADP-ribose) polymerase-1 activation, chronic inflammation, and oxidative stress in COPD patients.” Free-Radic-Biol-Med. 35(2): 140-8), using a rabbit-anti-poly(ADP-ribose). Transcription of TNF-alpha, IL-1/? and MIP-2 was determined in aortic tissues by RT-PCR.
  • mice After 12 weeks, mice develop mild atherosclerosis with predominantly initial lesions. Addition of 2 or more PARP-inhibitors to the standard diet reduces the number of atherosclerotic lesions and the plaque size, and reduces the production of pro ⁇ inflammatory cytokines of aortic tissues (Table 12). No pathological effects are observed of the experimental diets in wild-type mice.
  • Example 5 Reduction of inflammation and improved recovery after a hemorrhagic shock
  • Shock is a state in which adequate perfusion to sustain the physiologic needs of organ tissues is not present. Many conditions, including sepsis, blood loss, impaired autoregulation, and loss of autonomic tone, may produce shock or shock-like states. In hemorrhagic shock, blood loss exceeds the body's ability to compensate and provide adequate tissue perfusion and oxygenation. This frequently is due to trauma, but it may be caused by spontaneous hemorrhage, surgery, and other causes.
  • the patients experience an enhanced recovery with a reduction of time spent in hospital up to 20%.
  • the animals are placed in supine position and allowed to breath spontaneously.
  • body temperature is maintained at 37°C with an infrared heating lamp controlled by a thermo analyzer system (Hugo Sachs Elektronik, March-Hugstetten, Germany) connected to a rectal probe.
  • the skin over the left femoral area is shaved and disinfected with povidon iodine.
  • rats are subjected to hemorrhage by withdrawing blood in quantities of 2.1 ml/100 g body weight (representing approx. 30-40% of circulating volume) at a rate of 1 mL/min. Both heart rate and blood pressure are monitored during 10 minutes. 10 minutes after induction of shock, the canule is removed and the incision is ligated.
  • Each compound or combination of compounds is administered to a group of 10 rats. Of each group, 5 rats are sham-treated (no blood withdrawn) and these serve as controls for potential side effects of the administered PARP-inhibitors.
  • Morin (M), fisetin (F), 1 ,7-dimethylxantine (X), theo- bromine (T), delphinidin (D) are administered intravenously directly after induction of the shock in the range of 5-50 mg/kg to achieve plasma concentrations of free plus conjugated compounds in the range of 1-10 ⁇ M.
  • Parameters measured are PARP-activation and apoptosis of the liver, levels of TNF-alpha, IL-6 and IFN-gamma in plasma, and infiltration of neutrophils (MPO activity) in the lungs.
  • Example 6 Reduction of tissue damage and inflammation in a renal ischemia- reperfusion model Ischemia is the condition suffered by tissues and organs when deprived of blood flow, which are mostly the effects of inadequate nutrient and oxygen supply.
  • Reperfusion injury refers to the tissue damage inflicted when blood flow is restored after an ischemic period of more than about ten minutes. Ischemia and reperfusion can cause serious brain damage in stroke or cardiac arrest.
  • the patients experience an enhanced recovery after the operation and a reduction of time spent in hospital up to 20%.
  • mice are anesthetized with sodium pentobarbital (100 mg/kg ip). Body temperature is maintained at 38 0 C by a heating pad. The skin over the abdomen is shaved and desinfected with povidone iodine solution. Under aseptic conditions, a 1.0-cm-long midline abdominal incision is made. Ischemia is induced by applying a nontraumatic vascular clamp to the left renal pedicle for 45 min. After 3 min, the kidney is inspected for signs of ischemia; subsequently, the wound is covered with cotton soaked in sterile phosphate-buffered saline (PBS). After 45 min ischemia, reperfusion is induced by removal of the clamp. The left kidney is inspected for restoration of blood flow and the contralateral kidney is removed and stored for further analysis. The wound is closed in two layers.
  • PBS sterile phosphate-buffered saline
  • mice are sacrificied. Organs and blood are collected for further analysis. Neutrophils are counted by examining 20 fields of vision per kidney section (3-4 sections per kidney) at 20Ox magnification in a blinded fashion. The presence of internucleosomal DNA cleavage in kidneys is investigated with a commercial ligase- mediated (LM)-polymerase chain reaction (PCR) assay kit (Apoalert, Clontech, Palo Alto,
  • CA Reverse Transcriptase
  • mice are sham-treated (no clamp) and these serve as controls for potential side effects of the administered PARP-inhibitors.
  • Morin (M), fisetin (F), 1 ,7- dimethylxantine (X), theobromine (T), delphinidin (D) are administered intravenously 15 min before removal of the clamp at doses of 10-50 mg/kg to achieve plasma concentrations of free plus conjugated compounds in the range of 1-10 ⁇ M.

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Abstract

L'invention concerne l'utilisation d'au moins deux composés, identifiés comme étant des inhibiteurs de PARP-1, dont le premier est un composé naturel de formule générale (II) à (V), et le second est un précurseur de NAD+, dans la préparation de médicaments et d'aliments fonctionnels ou nutraceutiques. Par ailleurs, l'invention concerne d'utilisation de ces composés ou de compositions pharmaceutiques renfermant ces composés comme agent anti-inflammatoire pour traiter l'inflammation aiguë ou chronique dans certains troubles ou maladies.
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