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WO2006024545A1 - Fused bicyclic natural compounds and their use as inhibitors of parp and parp-mediated inflammatory processes - Google Patents

Fused bicyclic natural compounds and their use as inhibitors of parp and parp-mediated inflammatory processes Download PDF

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Publication number
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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Prior art keywords
flavone
acid
dihydroxy
coumarin
trihydroxy
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PCT/EP2005/009514
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French (fr)
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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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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/12—Ketones
    • 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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • 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
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • 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
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • 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 
    • 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
    • A61K31/335—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
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • 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
    • A61K31/335—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
    • 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
    • A61K31/40—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
    • 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
    • A61K31/40—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
    • 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
    • A61K31/41—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
    • 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
    • A61K31/435—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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

The invention relates to the use of at least two compounds, of which the first compound is a natural compound of the general formula (II) to (V), which are identified as PARP-1 inhibitors and a second compound, which is an NAD+ precursor for preparing medicaments, medical foods or nutraceuticals. The invention also relates to the use of these compounds or pharmaceutical compositions comprising at least two of these compounds as anti-inflammatory agent for treating acute or chronic inflammation in certain diseases or disorders.

Description

FUSED BiCYCLSC NATURAL COMPOUNDS AND THEIR USE AS INHIBITORS OF PARP AND PARP-MEDIATED INFLAMMATORY PROCESSES
FIELD OF THE INVENTION 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.
BACKGROUND OF THE INVENTION
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 large variety of chemical compounds displaying PARP-inhibitory activity and their potential application are described, for instance in Virag L. & Szabo C: Pharmacol-Rev. 2002, 54(3): 375-429. Most of these synthetic PARP-inhibiting compounds are very strong, and applicable for short administration periods, for instance during cancer chemotherapy, upon acute and serious inflammation, or upon ischemia and reperfusion damage in the brains, hart and kidneys. A long-term application of these chemical compounds, however, is not recommended in view of the toxic effects of these molecules, such as the inhibition of DNA repair, the promotion of tumour formation, or the increasing risk towards tumour formation. There, however, continues to be a need for effective PARP inhibitors, which produce minimal side-effects and which are applicable in long-term treatment.
DESCRIPTION OF THE INVENTION
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. Until now, no anti-inflammatory compounds are available for use in preventing, treating anά/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.
These natural occurring compounds can be used alone, or in mixtures comprising at least two compounds, preferably at least one of said compounds being a PARP-1 inhibitor compound and one being an NAD+-precursor. Accordingly, the present invention encompasses NAD+-precursors as PARP-1 inhibitor compound. In addition, the NAD+- precursors may be included to ensure optimal NAD+-status and energy metabolism in mitochondria. Specifically, 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+. When 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.
More specific, 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. As such, the term "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.
In a first embodiment, the present invention provides compounds of the formula (I)
Figure imgf000004_0001
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, -OCH3, -NH-CO-CH3, or
Figure imgf000004_0002
and wherein:
R3, R4, R5, R6 and R7 are independently chosen from hydrogen, hydroxyl, alkyl, double bounded oxygen, -OCH3, or -NH-CO-CH3, -O-glucose or -O-raffinose;
X is -CHR8- or, -NR9-, where R8 is hydrogen, hydroxyl, lower alkyl, -OCH3 or -NH-CO-
CH3 and R9 is hydrogen, hydroxyl or lower alkyl;
Y is -CHR10- or, -NR11-, where R10 is hydrogen, hydroxyl, lower alkyl, -OCH3 or -NH-
CO-CH3 and R11 is hydrogen, hydroxyl or lower alkyl;
R1, when present, is hydrogen, hydroxyl, amino, double bonded oxygen Or-OCH3; and
R2, when present, is hydrogen, hydroxyl, amino, double bonded oxygen Or-OCH3.
In a more specific embodiment, these natural PARP-1 inhibitor compounds belong to the family of the xanthines and are generally represented by the formula (II)
Figure imgf000005_0001
or by pharmaceutically acceptable salts, hydrates, esters, solvates, prodrugs, derivatives, metabolites or stereoisomers thereof, wherein:
R1 and R3, when present, are independently chosen from hydrogen and methyl;
R2, R4 and R7, when present, are independently chosen from hydrogen and double bonded oxygen;
R5, when present, is either hydrogen or
Figure imgf000005_0002
and R6, when present, is either hydrogen, methyl or
Figure imgf000005_0003
In yet more preferred embodiments, 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. Specifically preferred embodiments of the invention relate to the use of 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.
In a further specific embodiment, these natural PARP-1 inhibitor compounds belong to the family of the coumarines and are generally represented by the formula (III)
Figure imgf000006_0001
or by pharmaceutically acceptable salts, hydrates, esters, solvates, prodrugs, derivatives, metabolites or stereoisomers thereof, wherein: R1, R2, R3, R4, R5 and R6 are each independently chosen from hydrogen, hydroxyl, methyl, methoxy, COOH and -NH-CO-CH3
In yet more preferred embodiments, 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. Specifically preferred embodiments of the invention relate to the use of a compound selected from the group consisting of 3-acetamido-coumarin, 6-acetamido-coumarin, auraptene, coumarin, coumarin-3-carboxylic acid, daphnetin (7,8-dihydroxy-coumarin), 5,7-dihydroxy-4- methylcoumarin, 6,7-dihydroxy-4-methylcoumarin, fraxetin (7,8-dihydroxy-6-methoxy- coumarin), 7-hydroxycoumarin (umbelliferone), 4-methyldaphnetin (7,8-dihydroxy-4- methylcoumarin) and scoparone (6,7-dimethoxy-coumarin) as a medicine, for the preparation of a medicament, as an anti-inflammatory agent, or as (an additive in) nutraceuticals or functional or medical food.
In a further specific embodiment, these compounds belong to the family of the flavonoids and are generally represented by the formula (IV)
Figure imgf000006_0002
or by pharmaceutically acceptable salts, hydrates, esters, solvates, prodrugs, derivatives, metabolites or stereoisomers thereof, wherein: either R1 or R2 is phenyl, having one to five substituents which are independently chosen from hydrogen and hydroxyl, with the proviso that when R1 or R2 is not phenyl, it is hydrogen or hydroxyl; and R3, R4, R5 and R6, when present, are independently chosen from hydrogen and hydroxyl.
As used herein and unless otherwise stated, the term "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. For instance, 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. In this respect, caffeine can also be considered a pro-drug. Caffeine (1 ,3,7-trimethylxanthine), which has no PARP-inhibiting activity, is metabolized in the liver into 1 ,7-dimethylxanthine (paraxanthine), which is a PARP-inhibitor. The term "pro-drug" as used herein 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.
The term "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. Unless otherwise mentioned or indicated, the 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.
Whenever the term "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. The term "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. This term also refers to the compounds as depicted in Tables 1 to 6 and their derivatives, salts, solvates, hydrates, stereoisomeric forms, pro-drugs, esters and metabolites. For therapeutic use, the salts of the compounds according to the invention are those wherein the counter-ion is pharmaceutically or physiologically acceptable.
In yet more preferred embodiments, 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. Specifically preferred embodiments of the invention relate to the use of a compound selected from the group consisting of 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-flavone), myricetine (cannabiscetin; 3,5,7,3',4',5'- hexahydroxy-flavone), naringenin (4',5,7-trihydroxy-flavanone), quercetin (3,3',4',5,7- pentahydroxyflavone), taxifolin (3,5,7,3',4'-penta-hydroxy-flavanone) and tricetine (5,7,3',4',5'-pentahydroxy-flavone) as a medicine, for the preparation of a medicament, as an anti-inflammatory agent, or as (an additive in) nutraceuticals, or functional or medical food.
It should be noted that also encompassed by the invention is the use of any of the compounds of formula (IV), i.e. flavonoid compounds, as described above, wherein said compound is in the form of its dihydrate-derivative, such as, for instance quercetin dihydrate.
According to the invention, the expression "derivative thereof" thus also relates to a dihydrate derivate of any of the compounds described herein. In a still further specific embodiment, these PARP-1 inhibitor compounds of formula (I) belong to the family of the anthocyanidins, and are generally represented by the formula (V)
or by pharmaceutically acceptable salts, hydrates, esters, solvates, prodrugs, derivatives, metabolites or stereoisomers thereof, wherein:
R1 and R2 are independently chosen from hydrogen, hydroxy! and methoxy. In yet more preferred embodiments, 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. Specifically preferred embodiments of the invention relate to the use of 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)
Figure imgf000010_0001
or to pharmaceutically acceptable salts, hydrates, esters, solvates, prodrugs, derivatives, metabolites or stereoisomers thereof, for instance for use as anti-inflammatory agents, wherein R1, R2, R3, R4, R5, R6 and R7 are independently chosen from hydrogen, hydroxyl or methoxy.
In a more preferred embodiment, 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. Specifically preferred embodiments of the invention relate to the use of a compound selected from the group consisting of anhydro-podorhizol, deoxypodo-phyllotoxin, enterodiol, enterolactone, 7-hydroxy-matairesinol, lariciresinol, matairesinol, 6-methoxy-podophyllo-toxin, yS-peltatin, pinoresinol, podophyllo-toxin, secoisolarici-resinol and vatein as a medicine, 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.
Specifically preferred embodiments of the invention relate to the use of a compound selected from the group consisting of allantoin, amentoflavone (didemethyl-ginkgetin), camosine (/?-alanyl-L-histidine), frans-cinnamic acid, m-coumaric acid, o-coumaric acid (trans-2-hydroxy-cinnamic acid), coumestrol (7,12-dihydroxy-coumestan), emodin (1 ,3,8- trihydroxy-6-methylanthra-quinone), #-lapachone, (-)-epicatechin((-)-cis-3,3',4',5,7-penta- hydroxyflavane), (-)-epigallo-catechin gallate, 18σ-glycyrrhetinic acid isoliquiritigenin (4,2',4'-trihydroxy-chalcone), khellin, 8-methoxypsoralen (xanthotoxin; methox-salen), naringin (4',5,7-trihydroxy-flavanone 7-rhamnoglucoside), oxypurinol, quercitrin, res- veratrol (3,5,4'-trihydroxy-ifrans-silbene), thymidine, thymo-quinone, allo-betulin, betulin, lupeol, nomilin and uvaol as a medicine, for the preparation of a medicament, as an anti¬ inflammatory agent, or as (an additive in) nutraceuticals, functional or medical food.
The compounds allo-betulin, betulin, lupeol, nomilin and uvaol belong to the group of triterpenoid compounds (or saponins).
According to another aspect of the invention, 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.
In addition, by using combinations of PARP-1 inhibitors, 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 μM, shows better PARP- inhibition related anti-inflammatory activity, than one of the individual compounds in a concentration of 10 μM.
Therefore, 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), xanthine, xanthosine, 3- acetamido-coumarin, 6-acetamido-coumarin, auraptene, coumarin, coumarin-3-carboxylic acid, daphnetin (7,8-dihydroxy-coumarin), 5,7-dihydroxy-4-methylcoumarin, 6,7-dihydroxy- 4-methylcoumarin, esculetin (6,7-dihydroxycoumarin), fraxetin (7,8-dihydroxy-6- methoxycoumarin), 4-hydroxycoumarin, 7-hydroxycoumarin (umbelliferone), 4-methyl- daphnetin (7,8-dihydroxy-4-methylcoumarin), scoparone (6,7-dimethoxy-coumarin), 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), flavone (2-phenyl-chromone), 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-flavone), myricetine (cannabiscetin; 3,5,7,3',4',5'- hexahydroxy-flavone), naringenin (4',5,7-trιhydroxy-flavanone), quercetin (3,3',4',5,7- pentahydroxy-flavone), taxifolin (S.δ^^'^'-penta-hydroxy-flavanone), tricetine (5,7,3',4',S'- pentahydroxy-flavone), cyanidine, 4'0-methyl-delphinidin, delphinidin, malvidin, pelargonidin, peonidin, petunidin, anhydro-podorhizol, deoxypodo-phyllotoxin, enterodiol, enterolactone, 7-hydroxy-matairesinol, matairesinol, 6-methoxy-podophyllo-toxin, β- peltatin, podophyllo-toxin, secoisolarici-resinol, yatein, allantoin, amentoflavone (didemethyl-ginkgetin), caffeic acid, camosine Gff-alanyl-L-histidine), catechine, chlorogenic acid, frans-cinnamic acid, m-coumaric acid, o-coumaric acid (frans-2-hydroxy- cinnamic acid), coumestrol (7,12-dihydroxy-coumestan), curcumin, ellagic acid, emodin (1 ,3,8-trihydroxy-6-methylanthra-quinone), (-)-epicatechin ((-^c/s-S.S'^'.δJ-pentahydroxy- flavane), (-)-epigallo-catechin gallate, 18σ-glycyrrhetinic acid, 18/?-glycyrrhetinic acid, L- homocarnosine, isoliquiritigenin (4,21,4'-trihydroxy-chalcone), isonicotinamide, khellin, β- lapachone, lariciresinol, 8-methoxypsoralen (xanthotoxin; methoxsalen), naringin (4',5,7- trihydroxy-flavanone 7-rhamnoglucoside), oxypurinol, pinoresinol, purpurin (an anthraquinoid), quercitrin, resveratrol (3,5,4'-trihydroxy-frans-silbene), thymidine, thymoquinone, allo-betulin, betulin, lupeol, nomilin and uvaol, or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, derivative, metabolite or stereoisomer of any of said compounds. Preferably, in the compositions according to the invention, including pharmaceutical compositions, compounds belonging to a chemica] distinct class of compounds (i.e. as represented in the separate Tables 1 , 2, 3, 4, 5 and 6) are mixed.
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. Preferably, the invention relates to the use of 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-pyridiniums, such as 1-methyl- pyridinium, 1 ,4-dimethylpyridinium; or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, derivative, metabolite or stereoisomer of any of said NAD+ precursors. The expression "pyrolysis products of trigonelline" relates to compounds that are formed when trigonelline is heated, for instance during roasting of coffee beans. As such, the invention also encompasses these pyrolysis products as compounds of the invention.
Preferably, 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. More specific, 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). 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 .
According to a further embodiment, 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. Preferably, the invention relates to the use of 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 alkylpyridiniums, such as 1- methylpyridinium, 1 ,4-dimethylpyridinium; or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, derivative, metabolite or stereoisomer of any of said NAD+ precursors.
In this respect, it should be further understood that in cancerous cells that have a more anaerobic metabolism, PARP-1 inhibitor compounds may act by promoting apoptotic cell death. According to a further embodiment, 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. Preferably, the invention relates to the use of 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-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
According to a further embodiment, 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. muscle, skin, nervous tissues, vascular tissue), 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. Preferably, the invention relates to the use of 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-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.
According to a further embodiment, 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. Preferably, the invention relates to the use of 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-pyridiniums, such as 1- methylpyridinium, 1 ,4-dimethylpyridinium; or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, derivative, metabolite or stereoisomer of any of said NAD+ precursors. According to a preferred embodiment, said neurodegenerative diseases is Alzheimer's disease, Parkinson's disease or amyotrophic lateral sclerosis (ALS). According, to preferred embodiments, the invention relates to the uses of compositions as described above, wherein the inclusion of an NAD+ precursor is optional.
Thus, in one embodiment, 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, coumaήn, coumarin-3-carboxylic acid, daphnetin (7,8-dihydroxy-coumarin), 5,7-dihydroxy- 4-methylcoumarin, 6,7-dihydroxy-4-methylcoumarin, esculetin (6,7-di-hydroxycoumarin), fraxetin (7,8-dihydroxy-6-methoxycoumarin), 4-hydroxycoumarin, 7-hydroxycoumarin (umbelliferone), 4-methyl-daphnetin (7,8-dihydroxy-4-methylcoumarin), scoparone (6,7- dimethoxy-coumarin), aplgenin (4',5,7-trihydroxy-flavone), baicalein (5,6,7-trihydroxy- flavone), chrysine (5,7-dihydroxy-flavone), daidzein (4',7-dihydroxyisofiavone), fisetin (5- deoxyquercetin; 3,3',4',7-tetrahydroxyflavone), flavone (2-phenyl-chromone), 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-flavone), myricetine (cannabiscetin; 3,5,7,3',4',5'-hexahydroxy-flavone), naringenin (4',5,7-tri-hydroxy- flavanone), quercetin (3,3',4',5,7-pentahydroxy-flavone), tax/fol/n (3,5,7,3',4'-penta- hydroxy-flavanone), tricetine (5,7,3',4',5'-pentahydroxy-flavone), cyanidine, 4'0-metbyl- delphinidin, delphinidin, malvidin, pelargonidin, peonidin, petunidin, anhydro-podorhizol, deoxypodo-phyllotoxin, enterodiol, enterolactone, 7-hydroxy-matairesinol, matairesinol, 6- methoxy-podophyllo-toxin, /?-peltatin, podophyllo-toxin, secoisolarici-resinol, yatein, allantoin, amentoflavone (didemethyl-ginkgetin), caffeic acid, carnosine (/?-alanyl-L- histidine), catechine, chlorogenic acid, /rans-cinnamic acid, m-coumaric acid, o-coumaric acid (fra/7s-2-hydroxy-cinnamic acid), coumestrol (7,12-dihydroxy-coumestan), curcumin, ellagic acid, emodin (1,3,8-trihydroxy-6-methylanthra-quinone), (-)-epicatechin ((-)-c/s- 3,3',4',5,7-pentahydroxy-f/avane), (-)-epigaffo-catechin gallate, 18α-glycyrrhetinic acid, 18^-glycyrrhetinic acid, L-homocarnosine, isoliquiritigenin (4,2',4'-trihydroxy-chalcone), khellin, /?-lapachone, lariciresinol, 8-methoxypsoralen (xanthotoxin; methoxsalen), naringin (4',5,7-trihydroxy-flavanone 7-rhamnoglucoside), oxypurinol, pinoresinol, purpurin (an anthraquinoid), quercitrin, resveratrol (3,5,4'-trihydroxy-fr-aA?s-silbene), thymidine, thymoquinone, allo-betulin, betulin, lupeol, nomilin and uvaol, or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, derivative, metabolite or stereoisomer of any of said compounds.
It will be appreciated that 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. The invention further contemplates the use of a composition as described above, wherein said composition comprises at least two different poly (ADP-ribose) polymerase (PARP-1) inhibitor compounds as described herein, and an NAD+ precursor as described herein. According to another embodiment, 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. As an example, illustrating one of the specific embodiments of the invention represented in Tables 7 and 8, the invention relates to any of the uses as described above wherein 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 pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, derivative, metabolite or stereoisomer of any of said NAD+ precursors.
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), 18β- glycyrrhetinic acid, L-homocarnosine, isonicotinamide, nicotinamide (niacinamide/vitamin B3), nicotinic acid (niacin/vitamin B3) and purpurin (an anthraquinoid), or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, derivative, metabolite or stereoisomer of any of said compounds, as a medicine, for the preparation of a medicament, as an anti-inflammatory agent, or as (an additive in) nutraceuticals or medical food. According to still further embodiments of the invention, the compositions described herein may further comprise a pharmaceutically acceptable excipient or carrier.
The pharmaceutically acceptable salts of the compounds according to the invention, i.e. in the form of water-, oil-soluble, or dispersible products, include the conventional non-toxic salts or the quaternary ammonium salts which are formed, e.g., from inorganic or organic acids or bases. Examples of such 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, tosylate, and undecanoate. 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. Also, 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. For example, the compounds and compositions described herein may be used for inhibiting an inflammatory response by prevention of necrosis. According to another example, 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. According to another example, the compounds and compositions may be used for the prevention and/or the therapy of ischaemia and reperfusion damage. Other embodiments of the invention include the use of the compounds or compositions described herein for the inhibition of inflammatory processes mediated by NF-κB 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. 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.
According to the invention, 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. It may be understood that the term "patient" relates to mammals, especially humans.
In a specific embodiment, 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, coumarin-3-carboxylic acid, daphnetin (7,8-dihydroxy-coumarin), 5,7-dihydroxy- 4-methylcoumarin, 6,7-dihydroxy-4-methylcoumarin, esculetin (6,7-dihydroxycoumarin), fraxetin (7,8-dihydroxy-6-methoxycoumarin), 4-hydroxycoumarin, 7-hydroxycoumarin (umbelliferone), 4-methyl-daphnetin (7,8-dihydroxy-4-methylcoumarin), scoparone (6,7- dimethoxy-coumarin), 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-tetra-hydroxyflavone), flavone (2-phenyl-chromone), 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-tetrahydrc>xy-flavone), morin (2',3,4',5,7-pentahydroxy-flavone), myricetine (cannabiscetin; 3,5,7,3',4',5'-hexahydroxy-flavone), naringenin (4',5,7-trihydroxy- flavanone), quercetin (3,3',4',5,7-pentahydroxy-flavone), taxifolin (3,5,7,3',4'-penta- hydroxy-flavanone), tricetine (5,7,3',4',5'-pentahydroxy-flavone), cyanidine, 4'O-methyl- delphinidin, delphinidin, malvidin, pelargonidin, peonidin, petunidin, anhydro-podorhizol, deoxypodo-phyllotoxin, enterodiol, enterolactone, 7-hydroxy-matairesinol, matairesinol, 6- methoxy-podophyllo-toxin, /?-peltatin, podophyllo-toxin, secoisolarici-resinol, yatein, allantoin, amentoflavone (didemethyl-ginkgetin), caffeic acid, carnosine (/?-alanyl-L- histidine), catechine, chlorogenic acid, frans-cinnamic acid, m-coumaric acid, o-coumaric acid (frans-2-hydroxy-cinnamic acid), coumestrol (7,12-dihydroxy-coumestan), curcumin, ellagic acid, emodin (1 ,3,8-trihydroxy-6-methylanthra-quinone), (-)-epicatechin ((-)-c/s- 3,3',4',5,7-pentahydroxy-flavane), (-)-epigallo-catechin gallate, 18σ-glycyrrhetinic acid, 18/?-glycyrrhetinic acid, L-homocamosine, isoliquiritigenin (4,2',4'-trihydroxy-chalcone), khellin, /?-lapachone, lariciresinol, 8-methoxypsoralen (xanthotoxin; methoxsalen), naringin (4',5,7-trihydroxy-flavanone 7-rhamnoglucoside), oxypurinol, pinoresinol, purpurin (an anthraquinoid), quercitrin, resveratrol (3,5,4'-trihydroxy-frans-silbene), thymidine, thymoquinone, allo-betulin, betulin, lupeol, nomilin and uvaol, or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, derivative, metabolite or stereoisomer of any of said compounds. Preferably, the method for preventing, treating and/or alleviating inflammatory process, cancer, fibrosis, autoimmune diseases or neurodegenerative diseases according to the invention 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.
As such, 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 comprising at least two compounds, wherein 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-methylcoumarin, 6,7-dihydroxy-4-methylcoumarin, esculetin (6,7-dihydroxycoumarin), fraxetin (7,8-dihydroxy-6-methoxycoumarin), A- hydroxy-coumarin, 7-hydroxycoumarin (umbelliferone), 4-methyl-daphnetin (7,8- dihydroxy-4-methylcoumarin), scoparone (6,7-dimethoxy-coumarin), baicalein (5,6,7- trihydroxy-flavone), daidzein (4',7-dihydroxyisoflavone), fisetin (5-deoxyquercetin; 3,3',4',7- tetra-hydroxyflavone), flavone (2-phenyl-chromone), galangin (3,5,7-trihydroxy-flavone), gossypetin (3,5,7,8>3',4'-hexahydroxy-flavone), kaempferol (robigenin; 3,4',5,7-tetra- hydroxy-flavone), morin (2',3,4',5,7-pentahydroxy-flavone), myricetine (cannabiscetin; S^J^'^'^'-hexahydroxy-flavone), naringenin (4',5,7-trihydroxy-flavanone), quercetin (3,3',4',5,7-pentahydroxy-flavone), taxifolin (3,5,7,3',4'-penta-hydroxy-flavanone), tricetine (δJ.S'^'.δ'-penta-hydroxy-flavone), cyanidine, 4'O-methyl-delphinidin, delphinidin, malvidin, pelargonidin, peonidin, petunidin, allantoin, amentoflavone (didemethyl- ginkgetin), caffeic acid, catechine, chlorogenic acid, trans-άnnamic acid, m-coumaric acid, o-coumaric acid (frans-2-hydroxy-cinnamic acid), coumestrol (7,12-dihydroxy- coumestan), ellagic acid, emodin (1 ,3,8-trihydroxy-6-methylanthra-quinone), (-)- epicatechin ((^-c/s-S.S'^'.δJ-pentahydroxy-flavane), (-)-epigallo-catechin gallate, 18α- glycyrrhetinic acid, 18/?-glycyrrhetinic acid, isoliquiritigenin (4,2',4'-trihydroxy-chalcone), khellin, /Mapachone, 8-methoxypsoralen (xanthotoxin; methoxsalen), naringin (4',5,7- trihydroxy-flavanone 7-rhamnoglucoside), oxypurinol, purpurin (an anthraquinoid), quercitrin, thymidine, thymoquinone, allo-betulin, betulin, lupeol, nomilin, uvaol and or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, derivative, metabolite or stereoisomer of any of said compounds, and is present in a dose of between about 50- 500 mg, and wherein a second compound is an NAD+ precursor 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 alkylpyridiniums, such as 1-methylpyridinium, 1 ,4- dimethylpyridinium; or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, derivative, metabolite or stereoisomer of any of said NAD+ precursors; and wherein said NAD+ precursor is present in dose of between 1 - 50 mg.
In order to use the PARP-1 inhibitor compounds of the present invention, they will normally be formulated into a pharmaceutical composition in accordance with pharmaceutical practice.
In therapeutic or prophylactic use, PARP-1 inhibitors may be administered by any route that drugs are conventionally administered. Such 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.
For patients with pulmonary diseases, therapeutic administration by inhalation is preferred.
Compounds or 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. When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil. In addition, 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. Further, a syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes, colorings, and flavorings. It will be appreciated that the form and character of the pharmaceutically acceptable carrier is dictated by the amount of active ingredient with which it is to be combined, the route of administration and other well-known variables. 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. Examples of 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 based solutions. Dosage
As used herein, 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. According to a more specific embodiment, 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. Preferably, said plasma concentration is between 0.1 and 50 μM or between 0.5 and 40 μM, more preferably, said plasma concentration is between 1 and 30 μM, or between 2 and 20 μM or between 5 and 15 μM or about 10 μM per compound. It will be appreciated by the person skilled in the art that plasma concentrations above 100 μM per compound toxic effects may occur for some of these compounds in normal human cells.
According to a more specific embodiment, the NAD+ precursors in the compositions according to the invention, including nutraceuticals, functional and medical foods, 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. Preferably, said plasma concentration is between 10 nM and 10 mM or between
100 nM and 1 mM, more preferably, said plasma concentration is between 1 μM and 100 μM, or between 2 and 50 μM or between 5 and 25 μM or about 10 μM per compound. For instance, in case of nicotinamide, whole blood (containing blood cells and plasma) concentrations are in the millimolar range.
Plasma concentrations above 50 μM of compounds may exert toxic effects in normal human cells. Preferably 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. Generally, 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 μg and preferably 10 to 200 μg 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. Depending on the mode of administration, e.g. oral or intraperitoneal, or any of the ones described above, the man skilled in the art knows how to define or calculate the actual dose to be administered to a patient.
In a preferred embodiment, 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. Generally, 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. It will be appreciated by the person skilled in the art that intracellular NAD+ concentrations may increase to reach a plateau when the daily intake of nicotinic acid or niacin is between 50 and 100 mg per day (Hageman et al. (1998) "Nicotinic acid supplementation: effects of niacin status, cytogenic damage, and poly(ADP-ribosylation) in lymphocytes of smokers." Nutr.-Cancer 32:113-120). In case the daily intake of nicotinic acid or niacin is substantially more than 100 mg per day, flushing may occur.
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. In an embodiment, the second compound is administered simultaneously with, separate from or sequential to said first compound. In all aspects of the invention, 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. When compounds of the invention include an acidic function, such as a carboxy group, then 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. Nutraceuticals & medical foods
It will be appreciated that the compounds and compositions of the invention may be used as nutraceuticals, functional or medical food, or as additives in said nutraceuticals, functional or medical food
In a specific aspect, 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. Preferably, 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.
The term nutraceutical as used herein 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. Thus, in one embodiment 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.
In contrast to nutraceuticals, the so-called "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. For instance, the patients may be treated before and/or after surgery with the medical foods of the invention.
Hence, the present invention contemplates a food or beverage comprising a nutraceυt\ca\ according to the invention.
Plants
It will be appreciated by the person skilled in the art that the term "pharmaceutical composition" encompasses plant extracts comprising at least one and preferably at least two of the PARP-1 inhibitor compounds of the present invention. In this regard, the term
"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. In other words, 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. According to the invention, extracts are prepared in three forms, semiliquid or of syrupy consistency, pilular or solid and as dry powder. Preferably, 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. Preferably, 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.
It will furthermore be appreciated by the person skilled in the art that 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. Preferably, the plant extracts are made from the plants of the family Cruciferae and Leguminosae / Fabaceae (bean family), preferentially
Pisum sativum, or sprouts therefrom.
Those skilled in the art will appreciate that numerous changes and modifications can be made to the preferred embodiments of the invention and that such changes and modifications can be made without departing from the spirit of the invention. It is, therefore, intended that the appended claims cover all such equivalent variations as fall within the true spirit and scope of the invention.
In addition, all terms used in the description of compounds of the present invention have their meaning as is well known in the art.
The disclosure of all patents, publications (including published patent publications), and database accession numbers and depository accession numbers referenced in this specification are specifically incorporated herein by reference in their entirety to the same extent as if each such individual patent, publication, and database accession number, and depository accession number were specifically and individually indicated to be incorporated by reference.
It is to be understood that the following figures and examples are meant to illustrate the embodiments of the present invention and are in no way to be construed as limiting the present invention. The invention may be practised other than as particularly described and still be within the scope of the accompanying claims.
EXAMPLES
Example 1 : PARP-1 inhibitors
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 μM, 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
The procedure of the ELISA-assay was as follows:
Human rPARP-1 (400 ng/ml) in Tris buffer (50 mM Tris-HCI, pH 8 + 20 μM ZnCI2 + 4 mM MgCI2 ) was immobilized on a polyvinylchloride microtiter plate (100 μl/well) overnight at 40C. After five washing steps with PBS-T (150 mM PBS pH 7.2 + 0.05% Tween 20), a reaction mixture was added to the wells (100 μl/well), containing 50 μM β-NAD+ (10% biotinylated β-NAD+, 90% unlabeled β-NAD+), 1 mM DTT, 1.25 μg/ml nicked DNA and 0- 200 μM test compounds in Tris buffer, pH 8.0. Nicked DNA was prepared as follows: Calf thymus DNA (0.25 mg/ml) was incubated in Tris buffer (50 mM Tris-HCI (pH 7.5) + 5 mM MgCI2 + 0.5 mg/ml BSA) with 10 ng/ml Dnase I at 37°C during 40 minutes, at 77°C during 5 minutes and directly cooled at ice. rPARP-1 was incubated with the reaction mixture at 4°C during 1 hour. After five washing steps with PBS-T, the formation of poly(ADP-ribose)- polymers was detected with a one hour incubation at room temperature with 100 μl/well peroxidase-labeled streptavidin (diluted 1 :5000 in PBS-T+0.4% BSA). After final washing steps (three times with PBS-T and twice with H2O), incubation with 0.1 mg/ml 3, 3', 5,5'- tetramethylbenzidine (TMB) in the presence of 0.003% H2O2 in 0.11 M NaCH3COOH- buffer, pH 5.5, (100 μl/well) at 37°C during 15 minutes gave a positive reaction. The reaction was stopped by adding 0.75 M HCI (50 μl/well) and the absorbance was measured at 450 nm. To study effect test compounds, these compounds were added to the reaction mixture, solvent controls were included in triplicate.
Cell assay
In human epithelial lung cells (A549) and endothelial cells (RF24), PARP activation was induced by treating the cells with 300 μM H2O2 (hydrogen peroxide) or 25 μM MNNG (N- methyl-N'-nitro-nitrosoguanidine) for 30 minutes. NAD+ levels were measured. Treatment with MNNG was specifically applied for compounds with antioxidant activity. Treatments with H2O2 or MNNG resulted in a decrease in cellular NAD+ levels to values that are approximately 10-40% of those of untreated control cells. Evaluation of PARP-inhibiting activity involved pre-incubation for 15 minutes with the compounds tested (100 μM, or indicated if otherwise), after which cells were challenged with either 300 μM H2O2 or 25 μM MNNG for 30 minutes. This challenge results in a decrease of intracellular NAD+ after 30 min. to approximately 20-30% of the levels of unchallenged cells. In the presence of a PARP-inhibitor, the amount of NAD+ is less reduced, and this excess NAD+ when compared to cells challenged with H2O2 or MNNG without PARP-inhibitors, is the percentage listed Table 9. The level of NAD+ in unchallenged controls cells is set at 100%. This means that a level of 35% as listed in Table 9 implies that there is 35% more NAD+ present in the cells challenged with MNNG in presence this PARP-inhibitor (for instance, NAD+ reduces to 25% in cells challenged with MNNG without PARP-inhibitors, and is only reduced to 60% when challenged in presence of a PARP-inhibitor; the difference, 60 - 25 = 35% is listed in Table 9 to indicate the inhibitory potential).
Example 2. Amelioration of pulmonary and systemic inflammatory processes
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.
Daily use of these preparation slows down the progression of the disease (pulmonary dysfunction), and reduces the loss of muscle tissue and reduces exercise intolerance. This treatment improves the quality of life of patients with COPD.
Animal study
In a mouse model of chronic pulmonary inflammation the effects of combinations of PARP- inhibitors are evaluated (Vernooy et a/. (2002) "Long-term intratracheal lipopolysaccharide exposure in mice results in chronic lung inflammation and persistent pathology". Am-J- Respir-Cell-Mol-Biol. 26(1): 152-9).
Methods
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. In brief, mice are anesthetized by intraperitoneal injection of xylazin/ketamin. A volume of 50 μl is instilled intratracheally via a canule, followed by 0.1 ml of air. 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 μl 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 μM. Of each diet group, 5 mice are sham-treated with LPS-free saline and 5 mice are treated with LPS as described above. The following combinations are also evaluated: M+F, M+X, F+X, M+T, F+T, M+F+T, M+F+X, M+F+C, F+T+X, F+T+C, T+X+C, M+F+T+X, M+F+T+C, M+X+T+C, F+X+T+C, F+M+F+X+C. Pulmonary histopathology and inflammation are evaluated as described by Vemooy et al. (Vernooy et al., 2002 and Vemooy et al. (2001) "Intratracheal instillation of lipopolysaccharide in mice induces apoptosis in bronchial epithelial cells: no role for tumor necrosis factor-alpha and infiltrating neutrophils." Am-J-Respir-Cell-Mol-Biol. 24(5): 569- 76). PARP-activation is evaluated in pulmonary and skeletal muscle tissue sections by immunehistochemistry 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). In addition, skeletal muscle levels of NAD+ and ATP are analysed as well as mitochondrial oxidative capacity. Results
Effect of PARP-inhibitors on pulmonary and systemic inflammation and PARP-activation
Histological examination of H&E-stained lung tissue sections of mice repeatedly exposed to LPS (5 μg/mouse) twice per week for 12 wk demonstrates a striking inflammatory pattern after a 1-wk recovery period. First, lungs of LPS-challenged mice contain dense lymphocytic aggregates, which are observed ubiquitously in all parts of the lungs. Airway walls are thickened and smooth muscle layer increased. Transcription of TNF-alpha and PARP-activation (detected by immunohistochemistry) in pulmonary sections as well as in skeletal muscle sections from the tibialis are increased. It is observed that combinations of 2 or more compounds with PARP-inhibiting activity significantly reduce lymphocyte infiltrations, TNF-alpha production and PARP-activation in lungs and skeletal tissues, and pulmonary histology is improved when compared to pair-fed controls on a standard laboratory diet (Table 10). Muscle levels of NAD+ and ATP are increased and oxidative capacity of mitochondria is improved in mice receiving 2 or more PARP-inhibitors when compared to mice receiving standard lab chow. No pathological effects are observed of the experimental diets in sham-treated mice.
The other possible combinations listed in Table 8 provide essentially the same results.
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 blood cultures
The whole experiment was performed under sterile conditions.
Human whole blood was acquired by venapunction in blood tubes containing EDTA or heparin. Immediately hereafter, or after storage at 4 0C or 37 0C 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 0C 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 μg/ml) and the blood was incubated for 16 or 24 hours at 37 0C.
Finally, the blood samples were centrifuged and cytokine levels, e.g. IL-6, were determined in the plasma using standard ELISA techniques, immediately after centrifugation or after plasma storage at -20 0C.
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.
It will be evident that the PARP-1 compounds reduce the relative IL-6 concentration.
Next, 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.
These patients experience an improvement of vascular function, and a slowing of the progression of the disease with a reduced incidence of cardiovascular problems, retinal dysfunction and neuronal dysfunction.
Animal study
In a mouse model of vascular dysfunction induced by diabetes the effects of combinations of natural PARP-1 inhibitors are evaluated. Methods
Adult 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. 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 μM. The following combinations are also evaluated: M+F, M+X, F+X, M+T, F+T, M+F+T, M+F+X, M+F+C, F+T+X, F+T+C, T+X+C, M+F+T+X, M+F+T+C, M+X+T+C, F+X+T+C, F+M+F+X+C.
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). Levels of pro-inflammatory cytokines (TNF-alpha, IL-1, IL- 6) are measured in plasma by ELISA. Immediately after excision a part of the aorta is snap-frozen and coupes are prepared for immunehistochemical evaluation of PARP- activation 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). Results
Effect of PARP-inhibitors on vascular function and inflammation
A significant loss of endothelial function is observed in streptozotocin-induced diabetic mice on the standard lab diet when compared to vehicle controls. Addition of 2 or more PARP- inhibitors to the standard diet of diabetic mice significantly improves vascular function, reduces plasma levels of pro-inflammatory cytokines, and reduces PARP-1 activation in endothelial cells (Table 11 ). No pathological effects are observed of the experimental diets in vehicle-treated mice.
The other possible combinations listed in Table 8 provide essentially the same results.
Example 4. Reduction of atherosclerotic plaque formation
Atherosclerotic plaques in small arteries of heart and brain that become unstable cause disruption of blood flow through part of the heart or brain, and this results in heart ischemia or stroke (in brain).
Patients with atherosclerotic plaques, which is evident from previously experienced heart ischemia or stroke, daily receiving 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, experience an improvement of vascular function and a reduced incidence of ischemic events (heart infarct or stroke). Animal study
In a mouse model of atherosclerotic plaque formation, the effects of combinations of PARP-inhibitors is evaluated. Methods
The effects of dietary supplementation with combinations of natural PARP-inhibitors on early occurring pro-inflammatory events in the aorta of apo-E knock-out (apo-E KO) mice are evaluated for a ten-week period, which is sufficient to detect early atherosclerotic plaque formation (Curfs et al. (2004) "Chronic exposure to the carcinogenic compound benzo[a]pyrene induces larger and phenotypically different atherosclerotic plaques in ApoE-knockout mice." Am. J. Pathol. 164(1): 101-8).
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 μM. The following combinations are also evaluated: M+F, M+X, F+X, M+T, F+T, M+F+T, M+F+X, M+F+C, F+T+X, F+T+C, T+X+C, M+F+T+X, M+F+T+C, M+X+T+C, F+X+T+C, F+M+F+X+C.
A group of 10 mice receives the standard diet without additions. Wild-type mice (10/group) receive the experimental diets and serve as controls for potential side effects.
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.
Results Effect of PARP-inhibitors on atherslerotic plaque formation and inflammation in apo-E knock-out 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.
The other possible combinations listed in Table 8 provide essentially the same results.
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.
Treatment of hemorrhagic shock: Methods are essentially as described in: Luyer et al. (Luyer et a/. (2004) "Enteral administration of high-fat nutrition before and directly after hemorrhagic shock reduces endotoxemia and bacterial translocation." Ann-Surg. 239(2): 257-64), but now using the PARP-1 compounds of the present invention.
Patients that have lost a large amount of blood due to serious trauma and suffer from hemorrhagic shock, are treated daily with specific nutritional supplements or preparations, which contain a combination of a NAD+-precursor and one or more of the PARP-inhibiting compounds listed in Tables 1-4 and 6.
The patients experience an enhanced recovery with a reduction of time spent in hospital up to 20%.
Animal study
In this model, male Sprague-Dawley rats (300-350 g) are used. The animals are weighed and the rat is anesthesized using inhalation-anesthesia.
The animals are placed in supine position and allowed to breath spontaneously. During surgery and throughout the experiment, 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.
An incision is made, the femoral artery dissected using aseptic technique and is cannulated with polyethylene tubing (PE-10) containing heparinized saline (10 Ill/ml). The arterial bloodpressure is continuously measured. The wound is covered with cotton soaked in sterile 0.9% NaCI.
After an acclimatization period of 30 minutes, 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.
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 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 μM. The following combinations are also evaluated: M+F, M+X, F+X, M+T, F+T, M+F+T, M+F+X, M+F+C, F+T+X, F+T+C, T+X+C, M+F+T+X, M+F+T+C, M+X+T+C, F+X+T+C, F+M+F+X+C. At t = 24h after induction of the shock, the rats are anesthesized. The skin over the abdomen is shaved and disinfected using povidon iodine. The abdomen is opened via midline-incision, blood samples are taken, and segments of the liver (200 mg) and the lungs are aseptically removed. The rat dies during anesthesia.
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.
Results
No pathological effects are observed in sham-treated rats. The 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 of the experimentally treated rats are comparable to the sham-treated rats, whereas the control rats (blood withdrawn, but no experimental diet) exhibit increased PARP-activation and apoptosis of the liver, infiltration of neutrophils (MPO activity) in the lungs and while the levels of TNF-alpha, IL-6 and IFN-gamma in plasma are increased (see Table 13). The other possible combinations listed in Table 8 provide essentially the same results.
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.
Treatment of ischemia/reperfusion damage in patients
Methods are essentially as described in De Vries et al. (De Vries et al. (2003) "Inhibition of complement factor C5 protects against renal ischemia-reperfusion injury: inhibition of late apoptosis and inflammation." Transplantation. 75(3): 375-82), but using the PARP-1 compounds of the present invention.
In this experiment, the treatment of patients that have to go through major surgical operations, for instance organ transplantations, during which the blood flow through organs/tissues has to be temporarily stopped is evaluated. During a period of one week to one day preceding this operation, patients are treated daily 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.
The patients experience an enhanced recovery after the operation and a reduction of time spent in hospital up to 20%.
Animal study
At the start of the experiments, mice are anesthetized with sodium pentobarbital (100 mg/kg ip). Body temperature is maintained at 380C 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.
At t = 24 hours after reperfusion, the 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) enabling semiquantitative measurement of the extent of apoptosis. Measurement of renal TNF-σ and M1P-2 levels is done by Reverse Transcriptase (RT)-PCR.
Of each group, 5 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 μM. The following combinations were also evaluated: M+F, M+X, F+X, M+T, F+T, M+F+T, M+F+X, M+F+C, F+T+X, F+T+C, T+X+C, M+F+T+X, M+F+T+C, M+X+T+C, F+X+T+C, F+M+F+X+C
Results
The patho-physiological effects observed of the PARP-1 treated mice, e.g. apoptosis, are less severe than in mice receiving no treatment (see Table 14).
The other possible combinations listed in Table 8 provide essentially the same results.
Table 1
Figure imgf000042_0001
Table 2
Figure imgf000043_0001
Table 3
Figure imgf000044_0001
Figure imgf000045_0001
Table 4
Figure imgf000045_0002
Table 5
6-Methoxy-
Anhydro- podophyllo- podorhizol toxin
Deoxypodo-
/3-Peltatin phyllotoxin
Enterodiol Pinoresinol
Figure imgf000046_0002
Podophyllo-
Enterolactone toxin
7-Hydroxy- Secoisolarici- matairesinol resinol
Figure imgf000046_0003
Figure imgf000046_0001
Figure imgf000047_0001
Table 6
Figure imgf000047_0002
Figure imgf000048_0001
Figure imgf000049_0001
Table 7
Figure imgf000050_0001
Figure imgf000051_0001
TABLE 8
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Table 9
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Table 10. Effect of combinations of natural PARP-1 inhibitors on parameters of pulmonary inflammation after chronic LPS treatment
Figure imgf000068_0001
Table 11. Effect of combinations of PARP-inhibitors on vascular function in diabetic mice
Figure imgf000069_0001
Table 12. Effect of combinations of PARP-inhibitors on atherosclerotic plaque formation and inflammation in apo-E knock-out mice.
Figure imgf000070_0001
Table 13. Effect of combinations of natural PARP-I inhibitors on organ damage and inflammation 24 h after hemorrhagic shock in rats
O
Figure imgf000071_0001
Table 14. Effect of combinations of PARP-inhibitors on organ damage and inflammation 24 h after renal ischemia/reperfusion
Figure imgf000072_0001

Claims

1. Use of a composition for the preparation of a medicament, medical food or nutraceutical for treating, preventing and/or alleviating a disease or disorder involving chronic or acute inflammatory processes, characterized in that said composition comprises at least two compounds, wherein 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-methyl-xanthine, 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-methylcoumarin, 6,7-dihydroxy-4- methylcoumarin, esculetin (6,7-dihydroxycoumarin), fraxetin (7,8-dihydroxy-6- methoxycoumarin), 4-hydroxycoumarin, 7-hydroxycoumarin (umbelliferone), 4-methyl- daphnetin (7,8-dihydroxy-4-methylcoumarin), scoparone (6,7-dimethoxy-coumarin), baicalein (5,6,7-trihydroxy-flavone), daidzein (4',7-dihydroxyisoflavone), fisetin (5- deoxyquercetin; 3,3',4',7-tetrahydroxyflavone), flavone (2-phenyl-chromone), galangin (3,5,7-trihydroxy-flavone), gossypetin (3,5,7,8,3',4'-hexa-hydroxy-flavone), kaempferol (robigenin; 3,4',5,7-tetrahydroxy-flavone), morin (2',3,4',5,7-pentahydroxy-flavone), myricetine (cannabiscetin; 3,5,7, 3',4',5'-hexahydroxy-flavone), naringenin (4',5,7- trihydroxy-flavanone), quercetin (3,3',4',5,7-pentahydroxy-flavone), taxifolin (3,5,7,3',4'- penta-hydroxy-flavanone), tricetine (δJjS'^'.δ'-penta-hydroxy-flavone), cyanidine, 4'O- methyl-delphinidin, delphinidin, malvidin, pelargonidin, peonidin, petunidin, allantoin, amentoflavone (didemethyl-ginkgetin), caffeic acid, catechine, chlorogenic acid, trans- cinnamic acid, m-coumaric acid, o-coumaric acid (frans-2-hydroxy-cinnamic acid), coumestrol (7,12-dihydroxy-coumestan), ellagic acid, emodin (1 ,3,8-trihydroxy-6- methylanthra-quinone), (-)-epicatechin ((^-c/s-S^'^'.δJ-pentahydroxy-flavane), (-)- epigallo-catechin gallate, 18σ-glycyrrhetinic acid, 18^-glycyrrhetinic acid, isoliquiritigenin (4,2',4'-trihydroxy-chalcone), khellin, /Mapachone, 8-methoxypsoralen (xanthotoxin; methoxsalen), naringin (4',5,7-trihydroxy-flavanone 7-rhamnoglucoside), oxypurinol, purpurin (an anthraquinoid), quercitrin, thymidine, thymoquinone, allo-betulin, betulin, lupeol, nomilin, uvaol, or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, derivative, metabolite or stereoisomer of any of said compounds, and wherein a second compound is an NAD+ precursor 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), i-methyM-pyridone-δ-carboxamide (4-PYR), and alkylpyridiniums, such as 1-methylpyridinium, 1 ,4-dimethylpyridinium, or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, derivative, metabolite or stereoisomer of any of said NAD+ precursors.
2. The use according to claim 1 , wherein said disease or disorder is chosen from the group consisting of acute or chronic inflammation, diabetes, atherosclerosis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease (IBD), rheumatoid arthritis, ischemia and reperfusion damage, and endotoxic or haemorrhagic shock.
3. Use of a composition for the preparation of a medicament, medical food or nutraceutical for treating, preventing and/or alleviating cancer, characterized in that said composition comprises at least two compounds, wherein 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-di methyl uric acid, 1-methyluric acid, 1-methyl-xanthine, 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-methylcoumarin, 6,7-dihydroxy-4- methylcoumarin, esculetin (6,7-dihydroxycoumarin), fraxetin (7,8-dihydroxy-6- methoxycoumarin), 4-hydroxycoumarin, 7-hydroxycoumarin (umbelliferone), 4-methyl- daphnetin (7,8-dihydroxy-4-methylcoumarin), scoparone (6,7-dimethoxy-coumarin), baicalein (5,6,7-trihydroxy-flavone), daidzein (4',7-dihydroxyisoflavone), fisetin (5- deoxyquercetin; 3,3',4',7-tetrahydroxyflavone), flavone (2-phenyl-chromone), galangin (3,5,7-trihydroxy-flavone), gossypetin (3,5,7,8,3',4'-hexa-hydroxy-flavone), kaempferol (robigenin; 3,4',5,7-tetrahydroxy-flavone), morin (2',3,4',5,7-pentahydroxy-flavone), myricetine (cannabiscetin; S.δJ.S'^'.δ'-hexahydroxy-flavone), naringenin (4',5,7- trihydroxy-flavanone), quercetin (3,3',4',5,7-pentahydroxy-flavone), taxifolin (3,5,7,3',4f- penta-hydroxy-flavanone), tricetine (δJ.S'^'.δ'-penta-hydroxy-flavone), cyanidine, 4'O- methyl-delphinidin, delphinidin, malvidin, pelargonidin, peonidin, petunidin, allantoin, amentoflavone (didemethyl-ginkgetin), caffeic acid, catechine, chlorogenic acid, trans- cinnamic acid, m-coumaric acid, o-coumaric acid (frans-2-hydroxy-cinnamic acid), coumestrol (7,12-dihydroxy-coumestan), ellagic acid, emodin (1 ,3,8-trihydroxy-6- methylanthra-quinone), (-)-epicatechin ((-)-c/s-3,3',4',5,7-pentahydroxy-flavane), (-)- epigallo-catechin gallate, 1 δα'-glycyrrhetinic acid, 18^-glycyrrhetinic acid, isoliquiritigenin (4,2',4'-trihydroxy-chalcone), khellin, β-lapachone, 8-methoxypsoralen (xanthotoxin; methoxsalen), naringin (4',5,7-trihydroxy-flavanone 7-rhamnoglucoside), oxypurinol, purpurin (an anthraquinoid), quercitrin, thymidine, thymoquinone, aih-betulin, betulin, lupeol, nomilin, uvaol, or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, derivative, metabolite or stereoisomer of any of said compounds, and wherein a second compound is an NAD+ precursor 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 alkylpyridiniums, such as 1-methylpyridinium, 1 ,4-dimethylpyridinium, or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, derivative, metabolite or stereoisomer of any of said NAD+ precursors.
4. Use of a composition for the preparation of a medicament, medical food or nutraceutical for treating, preventing and/or alleviating fibrosis, characterized in that said composition comprises at least two compounds, wherein 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-methyl-xanthine, 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-methylcoumarin, 6,7-dihydroxy-4- methylcoumarin, esculetin (6,7-dihydroxycoumarin), fraxetin (7,8-dihydroxy-6- methoxycoumarin), 4-hydroxycoumarin, 7-hydroxycoumarin (umbelliferone), 4-methyl- daphnetin (7,8-dihydroxy-4-methylcoumarin), scoparone (6,7-dimethoxy-coumarin), baicalein (5,6,7-trihydroxy-flavone), daidzein (4',7-dihydroxyisoflavone), fisetin (5- deoxyquercetin; 3,3',4',7-tetrahydroxyflavone), flavone (2-phenyl-chromone), galangin (3,5,7-trihydroxy-flavone), gossypetin (3,5,7,8,3',4'-hexa-hydroxy-flavone), kaempferol (robigenin; 3,4',5,7-tetrahydroxy-flavone), morin (2',3,4',5,7-pentahydroxy-flavone), myricetine (cannabiscetin; S.δ^.S'^'.δ'-hexahydroxy-flavone), naringenin (4',5,7- trihydroxy-flavanone), quercetin (3,3',4',5,7-pentahydroxy-flavone), taxifolin (3,5,7,3\4'- penta-hydroxy-flavanone), tricetine (5,7,3',4',5'-pent.a-hydroxy-flavone), cyanidine, 4'O- methyl-delphinidin, delphinidin, malvidin, pelargonidin, peonidin, petunidin, allantoin, amentoflavone (didemethyl-ginkgetin), caffeic acid, catechine, chlorogenic acid, trans- cinnamic acid, m-coumaric acid, o-coumaric acid
Figure imgf000075_0001
acid), coumestrol (7,12-dihydroxy-coumestan), ellagic acid, emodin (1 ,3,8-trihydroxy-6- methylanthra-quinone), (-)-epicatechin ((-)-c/s-3,3',4',5,7-pentahydroxy-flavane), (-)- epigallo-catechin gallate, 18σ-glycyrrhetinic acid, 18/?-glycyrrhetinic acid, isoliquiritigenin (4,2',4'-trihydroxy-chalcone), khellin, β-\apachone, 8-methoxypsoralen (xanthotoxin; methoxsalen), naringin (4',5,7-trihydroxy-flavanone 7-rhamnoglucoside), oxypurinol, purpurin (an anthraquinoid), quercitrin, thymidine, thymoquinone, allo-betulin, betulin, lupeol, nomilin, uvaol, or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, derivative, metabolite or stereoisomer of any of said compounds, and wherein a second compound is an NAD+ precursor 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), i-methyW-pyridone-δ-carboxamide (4-PYR), and alkylpyridiniums, such as 1-methylpyridinium, 1 ,4-dimethylpyridinium, or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, derivative, metabolite or stereoisomer of any of said NAD+ precursors.
5. Use of a composition for the preparation of a medicament, medical food or nutraceutical for treating, preventing and/or alleviating autoimmune diseases, characterized in that said composition comprises at least two compounds, wherein 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-methyl-xanthine, 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-methylcoumarin, 6,7-dihydroxy-4- methylcoumarin, esculetin (6,7-dihydroxycoumarin), fraxetin (7,8-dihydroxy-6- methoxycoumarin), 4-hydroxycoumarin, 7-hydroxycoumarin (umbelliferone), 4-methyl- daphnetin (7,8-dihydroxy-4-methylcoumarin), scoparone (6,7-dimethoxy-coumarin), baicalein (5,6,7-trihydroxy-flavone), daidzein (4',7-dihydroxyisoflavone), fisetin (5- deoxyquercetin; 3,3',4',7-tetrahydroxyflavone), flavone (2-phenyl-chromone), galangin (3,5,7-trihydroxy-flavone), gossypetin (3,5,7,8,3',4'-hexa-hydroxy-flavone), kaempferol (robigenin; 3,4',5,7-tetrahydroxy-flavone), morin (2',3,4',5,7-pentahydroxy-flavone), myricetine (cannabiscetin; 3,5,7,3',4',5'-hexahydroxy-flavone), naringenin (4',5,7- trihydroxy-flavanone), quercetin (3,3',4',5,7-pentahydroxy-flavone), taxifolin (3,5,7,3',4'- penta-hydroxy-flavanone), tricetine (5,7,3',4',5'-penta-hydroxy-flavone), cyanidine, 4'O- methyl-delphinidin, delphinidin, malvidin, pelargonidin, peonidin, petunidin, allantoin, amentoflavone (didemethyl-ginkgetin), caffeic acid, catechine, chlorogenic acid, trans- cinnamic acid, m-coumaric acid, o-coumaric acid (frans-2-hydroxy-cinnamic acid), coumestrol (7,12-dihydroxy-coumestan), ellagic acid, emodin (1 ,3,8-trihydroxy-6- methylanthra-quinone), (-)-epicatechin ((-)-cis-3,3',4',5,7-pentahyάroxy-f\avane), (-)- epigallo-catechin gallate, 18α-glycyrrhetinic acid, 18^-glycyrrhetinic acid, isoliquiritigenin (4,2',4'-trihydroxy-chalcone), khellin, β-lapachone, 8-methoxypsoralen (xanthotoxin; methoxsalen), naringin (4',5,7-trihydroxy-flavanone 7-rhamnoglucoside), oxypurinol, purpurin (an anthraquinoid), quercitrin, thymidine, thymoquinone, allo-betulin, betulin, lupeol, nomilin, uvaol, or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, derivative, metabolite or stereoisomer of any of said compounds, and wherein a second compound is an NAD+ precursor 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 alkylpyridiniums, such as 1-methylpyridinium, 1 ,4-dimethylpyridinium, or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, derivative, metabolite or stereoisomer of any of said NAD+ precursors.
6. Use of a composition for the preparation of a medicament, medical food or nutraceutical for treating, preventing and/or alleviating neurodegenerative diseases, characterized in that said composition comprises at least two compounds, wherein 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-methyl-xanthine, 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-methylcoumarin, 6,7-dihydroxy-4- methylcoumarin, esculetin (6,7-dihydroxycoumarin), fraxetin (7,8-dihydroxy-6- methoxycoumarin), 4-hydroxycoumarin, 7-hydroxycoumarin (umbelliferone), 4-methyl- daphnetin (7,8-dihydroxy-4-methylcoumarin), scoparone (6,7-dimethoxy-coumarin), baicalein (5,6,7-trihydroxy-flavone), daidzein (4',7-dihydroxyisoflavone), fisetin (5- deoxyquercetin; 3,3',4',7-tetrahydroxyflavone), flavone (2-phenyl-chromone), galangin (3,5,7-trihydroxy-flavone), gossypetin (3,5,7,8,3',4'-hexa-hydroxy-flavone), kaempferol (robigenin; 3,4',5,7-tetrahydroxy-flavone), morin (2',3,4',5,7-pentahydroxy-flavone), myricetine (cannabiscetin; S.δJ.S'^'.δ'-hexahydroxy-flavone), naringenin (4',5,7- trihydroxy-flavanone), quercetin (3,3',4',5,7-pentahydroxy-flavone), taxifolin (3,5,7,3',4f- penta-hydroxy-flavanone), tricetine (δJ.S'^'.δ'-penta-hydroxy-flavone), cyanidine, 4'O- methyl-delphinidin, delphinidin, malvidin, pelargonidin, peonidin, petunidin, allantoin, amentoflavone (didemethyl-ginkgetin), caffeic acid, catechine, chlorogenic acid, trans- cinnamic acid, m-coumaric acid, o-coumaric acid (trans-2-hydroxy-cinnamic acid), coumestrol (7,12-dihydroxy-coumestan), ellagic acid, emodin (1 ,3,8-trihydroxy-6- methylanthra-quinone), (-)-epicatechin ((-)-c/s-3,3',4',5,7-pentahydroxy-flavane), (-)- epigallo-catechin gallate, 18σ-glycyrrhetinic acid, 18/?-glycyrrhetinic acid, isoliquiritigenin (4,2',4'-trihydroxy-chalcone), khellin, β~lapachone, 8-methoxypsoralen (xanthotoxin; methoxsalen), naringin (4',5,7-trihydroxy-flavanone 7-rhamnoglucoside), oxypurinol, purpurin (an anthraquinoid), quercitrin, thymidine, thymoquinone, allo-betulin, betulin, lupeol, nomilin, uvaol, or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, derivative, metabolite or stereoisomer of any of said compounds, and wherein a second compound is an NAD+ precursor 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 alkylpyridiniums, such as 1-methylpyridinium, 1 ,4-dimethylpyridinium, or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, derivative, metabolite or stereoisomer of any of said NAD+ precursors.
7. The use according to any of claims 1 to 6, wherein said composition comprises at least two different PARP-1 inhibitor compounds, wherein a second PARP-1 inhibitor compound is chosen from the group consisting of caffein (1,3,7-trimethylxanthine), 1 ,7- dimethyluric acid, 1-methyluric acid, 1-methyl-xanthine, 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-methylcoumarin, 6,7-dihydroxy- 4-methylcoumarin, esculetin (6,7-dihydroxycoumarin), fraxetin (7,8-dihydroxy-6- methoxycoumarin), 4-hydroxycoumarin, 7-hydroxycoumarin (umbelliferone), 4-methyl- daphnetin (7,8-dihydroxy-4-methylcoumarin), scoparone (6,7-dimethoxy-coumarin), baicalein (5,6,7-trihydroxy-flavone), daidzein (4',7-dihydroxyisoflavone), fisetin (5- deoxyquercetin; 3,3',4',7-tetrahydroxyflavone), flavone (2-phenyl-chromone), galangin (3,5,7-trihydroxy-flavone), gossypetin (3,5,7,8,3',4'-hexa-hydroxy-flavone), kaempferol (robigenin; 3,4',5,7-tetrahydroxy-flavone), morin (2',3,4',5,7-pentahydroxy-flavone), myricetine (cannabiscetin; S.δ^.S'^'.δ'-hexahydroxy-flavone), naringenin (4',5,7- trihydroxy-flavanone), quercetin (3,3',4',5,7-pentahydroxy-flavone), taxifolin (3,5,7,3',4- penta-hydroxy-flavanone), tricetine (δJ.S'^'.δ'-penta-hydroxy-flavone), cyanidine, 4'O- methyl-delphinidin, delphinidin, malvidin, pelargonidin, peonidin, petunidin, allantoin, amentoflavone (didemethyl-ginkgetin), caffeic acid, catechine, chlorogenic acid, trans- cinnamic acid, m-coumaric acid, o-coumaric acid (fr-ans-2-hydroxy-cinnamic acid), coumestrol (7,12-dihydroxy-coumestan), ellagic acid, emodin (1 ,3,8-trihydroxy-6- methylanthra-quinone), (-)-epicatechin ((-)-c/s-3,3',41,5,7-pentahydroxy-flavane), (-)- epigallo-catechin gallate, 18α-glycyrrhetinic acid, 18^-glycyrrhetinic acid, isoliquiritigenin (4,2',4'-trihydroxy-chalcone), khellin, β-lapachone, 8-methoxypsoralen (xanthotoxin; methoxsalen), naringin (4',5,7-trihydroxy-flavanone 7-rhamnoglucoside), oxypurinol, purpurin (an anthraquinoid), quercitrin, thymidine, thymoquinone, allo-betulin, betulin, lupeol, nomilin, uvaol, or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, derivative, metabolite or stereoisomer of any of said compounds.
8. The use according to any of claims 1 to 7, wherein said composition comprises a combination of compounds as represented in Table 7 or 8.
9. Use of at least two compounds, wherein 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-methyl-xanthine, 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-methylcoumarin, 6,7-dihydroxy-4- methylcoumarin, esculetin (6,7-dihydroxycoumarin), fraxetin (7,8-dihydroxy-6- methoxycoumarin), 4-hydroxycoumarin, 7-hydroxycoumarin (umbelliferone), 4-methyl- daphnetin (7,8-dihydroxy-4-methylcoumarin), scoparone (6,7-dimethoxy-coumarin), baicalein (5,6,7-trihydroxy-flavone), daidzein (4',7-dihydroxy-isoflavone), fisetin (5- deoxyquercetin; 3,3',4',7-tetrahydroxyflavone), flavone (2-phenyl-chromone), galangin (3,5,7-trihydroxy-flavone), gossypetin (S.δJ.S.S'^'-hexa-hydroxy-flavone), kaempferol (robigenin; 3,4',5,7-tetrahydroxy-flavone), morin (2',3,4',5,7-pentahydroxy-flavone), myricetine (cannabiscetin; 3,5,7,3',4',5'-hexahydroxy-flavone), naringenin (4',5,7- trihydroxy-flavanone), quercetin (3,3',4',5,7-pentahydroxy-flavone), taxifolin (3,5,7,3,4'- penta-hydroxy-flavanone), tricetine (5,7,3',4',5'-penta-hydroxy-flavone), cyanidine, 4'O- methyl-delphinidin, delphinidin, malvidin, pelargonidin, peonidin, petunidin, allantoin, amentoflavone (didemethyl-ginkgetin), caffeic acid, catechine, chlorogenic acid, trans- cinnamic acid, m-coumaric acid, o-coumaric acid (frans-2-hydroxy-cinnamic acid), coumestrol (7,12-dihydroxy-coumestan), ellagic acid, emodin (1,3,8-trihydroxy-6- methylanthra-quinone), (-)-epicatechin ((-J-c/s-S^'^'.δJ-pentahydroxy-flavane), (-)- epigallo-catechin gallate, 18α-glycyrrhetinic acid, 18/?-glycyrrhetinic acid, isoliquiritigenin (4,2',4'-trihydroxy-chalcone), khellin, /?-lapachone, 8-methoxypsoralen (xanthotoxin; methoxsalen), naringin (4',5,7-trihydroxy-flavanone 7-rhamnoglucoside), oxypurinol, purpurin (an anthraquinoid), quercitrin, thymidine, thymoquinone, allo-betulin, betulin, lupeol, nomilin, uvaol, or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, derivative, metabolite or stereoisomer of any of said compounds, and wherein a second compound is an NAD+ precursor 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 alkylpyridiniums, such as 1-methylpyridinium, 1 ,4-dimethylpyridinium, or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, derivative, metabolite or stereoisomer of any of said NAD+ precursors, for the preparation of a functional food for treating, preventing and/or alleviating a disease as defined in any of claims 1 to 6.
10. The use according to any of claims 1 to 9, wherein said poly (ADP-ribose) polymerase (PARP-1) inhibitor compound is provided in a dose of between about 0.1 - 60 mg/Kg.
11. The use according to any of claims 1 to 10, wherein said NAD+ precursor is provided in a dose of between 0.1 - 60 mg/Kg.
12. The use according to any of claims 1 to 11, wherein said NAD+ precursor compound is administered simultaneously with, separate from or sequential to said poly
(ADP-ribose) polymerase (PARP-1) inhibitor compound.
13. Use of a pharmaceutical composition for the preparation of a medicament for treating, preventing and/or alleviating a disease or disorder involving chronic or acute inflammatory processes, characterized in that said composition comprises at least two compounds, wherein a first compound is a poly (ADP-ribose) polymerase (PARP-1) inhibitor compound of the formula (II):
Figure imgf000081_0001
or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, derivative, metabolite, stereoisomer thereof as an anti-inflammatory agent, wherein:
R1 and R3, when present, are independently chosen from hydrogen and methyl;
R2, R4 and R7, when present, are independently chosen from hydrogen and double bonded oxygen;
R5, when present, is either hydrogen or
Figure imgf000081_0002
and R6, when present, is either hydrogen, methyl or
Figure imgf000081_0003
and wherein a second compound is an NAD+ precursor 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-methyl-nicotinamide, 1- methyl-2-pyridone-5-carboxamide (2-PYR), 1-methyl-4-pyridone-5-carboxamide (4-PYR), and alkylpyridiniums, 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.
14. The use according to claim 13, wherein said compound of the formula (II) is 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) and theophylline (1 ,3-dimethylxanthine).
15. Use of a pharmaceutical composition for the preparation of a medicament for treating, preventing and/or alleviating a disease or disorder involving chronic or acute inflammatory processes, characterized in that said composition comprises at least two compounds, wherein a first compound is a poly (ADP-ribose) polymerase (PARP-1) inhibitor compound of the formula (III):
Figure imgf000082_0001
or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, derivative, metabolite, stereoisomer thereof, as an anti-inflammatory agent, wherein: R1, R2, R3, R4, R5 and R6 are each independently chosen from hydrogen, hydroxyl, methyl, methoxy, COOH and -NH-CO-CH3, and wherein a second compound is an NAD+ precursor 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-methyl-nicotinamide, 1- methyl-2-pyridone-5-carboxamide (2-PYR), 1-methyl-4-pyridone-5-carboxamide (4-PYR), and alkylpyridiniums, 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.
16. The use according to claim 15, wherein said compound of the formula (III) is chosen from the group consisting of 3-acetamido-coumarin, 6-acetamido-coumarin, auraptene, coumarin, coumarin-3-carboxylic acid, daphnetin (7,8-dihydroxy-coumarin), 5,7-dihydroxy-4-methylcoumarin, 6,7-dihydroxy-4-methylcoumarin, esculetin (6,7- dihydroxycoumarin), fraxetin (7,8-dihydroxy-6-methoxycoumarin), 4-hydroxycoumarin, 7- hydroxycoumarin (umbelliferone), 4-methyl-daphnetin (7,8-dihydroxy-4-methylcoumarin), and scoparone (6,7-dimethoxy-coumarin).
17. Use of a pharmaceutical composition for the preparation of a medicament for treating, preventing and/or alleviating a disease or disorder involving chronic or acute inflammatory processes, characterized in that said composition comprises at least two compounds, wherein a first compound is a poly (ADP-ribose) polymerase (PARP-1) inhibitor compound of the formula (IV)
Figure imgf000083_0001
or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, derivative, metabolite, stereoisomer thereof, as an anti-inflammatory agent, wherein: either R1 or R2 is phenyl, having one to five substituents which are independently chosen from hydrogen and hydroxyl, with the proviso that when R1 or R2 is not phenyl, it is hydrogen or hydroxyl; and
R3, R4, R5 and R6, when present, are independently chosen from hydrogen and hydroxyl; and wherein a second compound is an NAD+ precursor 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 -methyl-nicotinamide, 1- methyl-2-pyridone-5-carboxamide (2-PYR), 1-methyl-4-pyridone-5-carboxamide (4-PYR), and alkylpyridiniums, 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.
18. The use according to claim 17, wherein said compound of the formula (IV) is chosen from the group consisting of baicalein (5,6,7-trihydroxy-flavone), daidzein (4',7- dihydroxy-isoflavone), fisetin (5-deoxyquercetin; 3,3',4',7-tetrahydroxyflavone), flavone (2- phenyl-chromone), galangin (3,5,7-trihydroxy-flavone), gossypetin (3, 5, 7, 8, 3',4 -hexa- hydroxy-flavone), kaempferol (robigenin; 3,4',5,7-tetrahydroxy-flavone), morin (2',3,4',5,7- pentahydroxy-flavone), myricetine (cannabiscetin; 3,5,7,3\4',5'-hexahydroxy-flavone), naringenin (4',5,7-trihydroxy-flava-none), quercetin (3,3',4',5,7-pentahydroxy-flavone), taxifolin (3,5,7,3',4'-penta-hydroxy-flavanone), and tricetine (δJ.S'^'.δ'-pentahydroxy- flavone).
19. Use of a pharmaceutical composition for the preparation of a medicament for treating, preventing and/or alleviating a disease or disorder involving chronic or acute inflammatory processes, characterized in that said composition comprises at least two compounds, wherein a first compound is a poly (ADP-ribose) polymerase (PARP-1) inhibitor compound of the formula (V):
Figure imgf000084_0001
or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, derivative, metabolite, stereoisomer thereof, as an anti-inflammatory agent, wherein:
R1 and R2 are independently chosen from hydrogen, hydroxyl and methoxy, and wherein a second compound is an NAD+ precursor 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-methyl-nicotinamide, 1- methyl-2-pyridone-5-carboxamide (2-PYR), 1-methyl-4-pyhdone-5-carboxamide (4-PYR), and alkylpyridiniums, 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.
20. The use according to claim 19, wherein said compound of the formula (V) is chosen from the group consisting of cyanidine, 4'O-methyl-delphinidin, delphinidin, malvidin, pelargonidin, peonidin and petunidin.
21. The use according to any of claims 13 to 20, wherein said disease or disorder is chosen from the group consisting of acute or chronic inflammation, diabetes, atherosclerosis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease (IBD), rheumatoid arthritis, ischemia and reperfusion damage, and endotoxic or haemorrhagic shock.
22. A method for treating an inflammatory process in a patient comprising administering to a patient a therapeutically effective amount of at least two compounds, wherein 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-methyl-xanthine, 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-rnethylcoumarin, 6,7-dihydroxy-4- methylcoumarin, esculetin (6,7-dihydroxycoumarin), fraxetin (7,8-dihydroxy-6- methoxycoumarin), 4-hydroxycoumarin, 7-hydroxycoumarin (umbelliferone), 4-methyl- daphnetin (7,8-dihydroxy-4-methylcoumarin), scoparone (6,7-dimethoxy-coumarin), baicalein (5,6,7-trihydroxy-flavone), daidzein (4',7-dihydroxyisoflavone), fisetin (5- deoxyquercetin; 3,3',4',7-tetrahydroxyfiavone), flavone (2-phenyl-chromone), galangin (3,5,7-trihydroxy-flavone), gossypetin (S.δJ.δ.S'^'-hexa-hydroxy-flavone), kaempferol (robigenin; 3,4',5,7-tetrahydroxy-flavone), morin (2',3,4',5,7-pentahydroxy-flavone), myricetine (cannabiscetin; S.δJ.S'^'.δ'-hexahydroxy-flavone), naringenin (4',5,7- trihydroxy-flavanone), quercetin (3,3',4',5,7-pentahydroxy-flavone), taxifolin (3,5,7,3',4'- penta-hydroxy-flavanone), tricetine (δJ.S'^'.δ'-penta-hydroxy-flavone), cyanidine, 4'O- methyl-delphinidin, delphinidin, malvidin, pelargonidin, peonidin, petunidin, allantoin, amentoflavone (didemethyl-ginkgetin), caffeic acid, catechine, chlorogenic acid, trans- cinnamic acid, m-coumaric acid, o-coumaric acid (fr"a/7s-2-hydroxy-cinnamic acid), coumestrol (7,12-dihydroxy-coumestan), ellagic acid, emodin (1 ,3,8-trihydroxy-6- methylanthra-quinone), (-)-epicatechin ((-)-c/s-3,3',4',5,7-pentahydroxy-flavane), (-)- epigallo-catechin gallate, 18α-glycyrrhetinic acid, 18/?-glycyrrhetinic acid, isoliquiritigenin (4,2',4'-trihydroxy-chalcone), khellin, /Mapachone, 8-methoxypsoralen (xanthotoxin; methoxsalen), naringin (4',5,7-trihydroxy-flavanone 7-rhamnoglucoside), oxypurinol, purpurin (an anthraquinoid), quercitrin, thymidine, thymoquinone, allo-betulin, betulin, lupeol, nomilin, uvaol, or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, derivative, metabolite or stereoisomer of any of said compounds, and wherein a second compound is an NAD+ precursor 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 alkylpyridiniums, such as 1-methylpyridinium, 1 ,4-dimethylpyridinium, or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, derivative, metabolite or stereoisomer of any of said NAD+ precursors.
23. Use of at least two compounds, wherein 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-methyl-xanthine, 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-methylcoumarin, 6,7-dihydroxy-4- methylcoumarin, esculetin (6,7-dihydroxycoumarin), fraxetin (7,8-dihydroxy-6- methoxycoumarin), 4-hydroxycoumarin, 7-hydroxycoumarin (umbelliferone), 4-methyl- daphnetin (7,8-dihydroxy-4-methylcoumarin), scoparone (6,7-dimethoxy-coumarin), baicalein (5,6,7-trihydroxy-flavone), daidzein (4',7-dihydroxyisoflavone), fisetin (5- deoxyquercetin; 3,3',4',7-tetrahydroxyflavone), flavone (2-phenyl-chromone), galangin (3,5,7-trihydroxy-flavone), gossypetin (3,5,7,8,3',4'-hexa-hydroxy-flavone), kaempferol (robigenin; 3,4',5,7-tetrahydroxy-flavone), morin (2',3,4',5,7-pentahydroxy-flavone), myricetine (cannabiscetin; 3,5,7,3',4',5'-hexahydroxy-flavone), naringenin (4',5,7- trihydroxy-flavanone), quercetin (3,3',4',5,7-pentahydroxy-flavone), taxifolin (3,5,7,3',4'- penta-hydroxy-flavanone), tricetine (δJ.S'^'^'-penta-hydroxy-flavone), cyanidine, 4'O- methyl-delphinidin, delphinidin, malvidin, pelargonidin, peonidin, petunidin, allantoin, amentoflavone (didemethyl-ginkgetin), caffeic acid, catechine, chlorogenic acid, trans- cinnamic acid, m-coumaric acid, o-coumaric acid (ifraπs-2-hydroxy-cinnamic acid), coumestrol (7,12-dihydroxy-coumestan), ellagic acid, emodin (1 ,3,8-trihydroxy-6- tnethylanthra-quinone), (-)-epicatechin ((-)-c/s-3,3',4l,5,7-pentahydroxy-flavane), (-)- epigallo-catechin gallate, 18σ-glycyrrhetinic acid, 18/?-glycyrrhetinic acid, isoliquiritigenin (4,2',4'-trihydroxy-chalcone), khellin, β-lapachone, 8-methoxypsoralen (xanthotoxin; methoxsalen), naringin (4',5,7-trihydroxy-flavanone 7-rhamnoglucoside), oxypurinol, purpurin (an anthraquinoid), quercitrin, thymidine, thymoquinone, allo-betulin, betulin, lupeol, nomilin, uvaol, or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, derivative, metabolite or stereoisomer of any of said compounds, and wherein a second compound is an NAD+ precursor 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 alkylpyridiniums, such as 1-methylpyridinium, 1 ,4-dimethylpyridinium, or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, derivative, metabolite or stereoisomer of any of said NAD+ precursors, as a medicine, for the preparation of a medicament, as an anti-inflammatory agent, or as an additive in nutraceuticals or medical food.
24. Medicament, nutraceutical or medical food for treating, preventing and/or alleviating a disease or disorder involving chronic or acute inflammatory processes comprising at least two compounds, wherein 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-methyl-xanthine, 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-methylcoumarin, 6,7-dihydroxy-4-methylcoumarin, esculetin (6,7-dihydroxycoumarin), fraxetin (7,8-dihydroxy-6-methoxycoumarin), 4-hydroxycoumarin, 7-hydroxycoumarin (umbelliferone), 4-methyl-daphnetin (7,8-dihydroxy-4-methylcoumarin), scoparone (6,7- dimethoxy-coumarin), baicalein (5,6,7-trihydroxy-flavone), daidzein (4',7- dihydroxyisoflavone), fisetin (5-deoxyquercetin; 3,3',4',7-tetrahydroxyflavone), flavone (2- phenyl-chromone), galangin (3,5,7-trihydroxy-flavone), gossypetin (3,5,7, 8,3',4'-hexa- hydroxy-flavone), kaempferol (robigenin; 3,4',5,7-tetrahydroxy-flavone), morin (2',3,4',5,7- pentahydroxy-flavone), myricetine (cannabiscetin; S.δJ.S'^'.δ'-hexahydroxy-flavone), naringenin (4',5,7-trihydroxy-flavanone), quercetin (3,3',4',5,7-pentahydroxy-flavone), taxifolin (S.δJ.S'^'-penta-hydroxy-flavanone), tricetine (SJ.S'^'.δ'-penta-hydroxy-flavone), cyanidine, 4'O-methyl-delphinidin, delphinidin, malvidin, pelargonidin, peonidin, petunidin, allantoin, amentoflavone (didemethyl-ginkgetin), caffeic acid, catechine, chlorogenic acid, frans-cinnamic acid, m-coumaric acid, o-coumaric acid (frans-2-hydroxy-cinnamic acid), coumestrol (7,12-dihydroxy-coumestan), ellagic acid, emodin (1 ,3,8-trihydroxy-6- methylanthra-quinone), (-)-epicatechin ((-)-c/s-3,3',4',5,7-pentahydroxy-flavane), (-)- epigallo-catechin gallate, 18σ-glycyrrhetinic acid, 18/?-glycyrrhetinic acid, isoliquiritigenin (4,2',4'-trihydroxy-chalcone), khellin, /?-lapachone, 8-methoxypsoralen (xanthotoxin; methoxsalen), naringin (4',5,7-trihydroxy-flavanone 7-rhamnoglucoside), oxypurinol, purpurin (an anthraquinoid), quercitrin, thymidine, thymoquinone, allo-betulin, betulin, lupeol, nomilin, uvaol, or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, derivative, metabolite or stereoisomer of any of said compounds, and is present in a dose of between about 50-500 mg, and wherein a second compound is an NAD+ precursor 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 alkylpyridiniums, such as 1-methylpyridinium, 1 ,4-dimethylpyridinium, or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, derivative, metabolite or stereoisomer of any of said NAD+ precursors, and is present in a dose of between 1 - 50 mg.
25. Food or beverage comprising a nutraceutical according to claim 24.
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