MXPA99011815A - Parp inhibitors, pharmaceutical compositions comprising same, and methods of using same - Google Patents

Abstract

A compound which inhibits PARP activity and effects a neuronal activity not mediated by NMDA.

Description

PARP INHIBITORS, PHARMACEUTICAL COMPOSITIONS THAT UNDERSTAND THEM, AND METHODS FOR USING THEM BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to inhibitors of the polymerase nucleic enzyme of poly (5 '-diphospho-ribose adenosine) ["polymerase of poly (ADP-ribose)" or "PARP" , which is sometimes also referred to as "PARS" by poly (ADP-ribose) synthetase]. More particularly, the invention relates to the use of PARP inhibitors to prevent and / or treat tissue damage resulting from cell damage or death due to necrosis or apoptosis; damage of the neural tissue resulting from ischemia and reperfusion injury; neurological disorders and neurodegenerative diseases; to prevent or treat vascular embolism; to treat or prevent cardiovascular disorders; to treat other conditions and / or disorders, such as age-related macular degeneration, AIDS, and other immune senescence diseases, arthritis, atherosclerosis, cachexia, cancer, skeletal muscle degenerative diseases involving replicative senescence, diabetes, trauma of the head, immune senescence, inflammatory bowel disorders (such as colitis and Crohn's disease), muscular dystrophy, osteoarthritis, osteoporosis, chronic and acute pain (such as neuropathic pain), renal failure, retinal ischemia, septic shock (such as endotoxic shock) ), and aging of the skin; to prolong the life span and the proliferative capacity of the cells; to alter the genetic expression of senescent cells; or to radiosensitize hypoxic tumor cells. 2. Description of the Prior Art Polymerase of poly (ADP-ribose is an enzyme located in the nuclei of cells of different organs, including muscle, heart and brain cells.) PARP has a physiological role in the repair of breaks of chains in DNA Once activated by damaged DNA fragments, PARP catalyzes the binding of up to 100 units of ADP-ribose with a variety of nuclear proteins, including histones and PARP itself, although the range has not been fully established. Because of the precise nature of PARP functions, it is thought that this enzyme plays a role in improving DNA repair, however, during increased cell stresses, the extensive activation of PARP can rapidly lead to cellular damage or death due to depletion of Energy stores: Four ATP molecules are consumed per NAD molecule (the source of ADP-ribose) regenerated. Consequently, the NAD, the substrate of PARP is depleted by the massive activation of PARP, and in the efforts to re-synthesize the NAD, the ATP can also be depleted. PARP activation has been reported to play a key role in neurotoxicity both induced by NMDA and by NO, as shown by the use of PARP inhibitors to prevent this toxicity in cortical cultures in proportion to their potency as inhibitors of this enzyme (Zhan et al., "Nitric Oxide Activation of Poly (ADP-Ribose) Synthetase in Neurotoxicity", Science, 263: 687-89 (1994)); and in hippocampal slices (Wallis et al., "Neuroprotection Against Nitric Oxide Injury with Inhibitors of ADP-Ribosylation", NeuroReport, 5: 3, 245-48 (1993)). Therefore, the potential role of PARP inhibitors in the treatment of neurodegenerative diseases and head trauma has been known. However, research continues to point out the exact mechanisms of its health effect on cerebral ischemia (Endres et al., "Ischemic Brain Injury is Mediated by the Activation of Poly (ADP-Ribose) Polymerase", J. "Cereb. Blood Flow Metabol., 17: 1143-51 (1997)), and in traumatic brain injury (Wallis et al., "Traumatic Neuroprotection with Inhibitors of Nitric Oxide and ADP-Ribosylation, Brain Res., 710: 169-77 (1996). It has been shown that simple injections of PARP inhibitors have reduced the infarct size caused by ischemia and reperfusion of the heart or skeletal muscle in rabbits., a single injection of the PARP inhibitor, 3-amino-benzamide (10 milligrams / kilogram), either one minute before the occlusion, or one minute before reperfusion, caused similar reductions in the size of the infarction in the heart (from 32 to 42 percent). Another inhibitor of PARP, 1,5-dihydroxyisoquinoline (1 milligram / kilogram), reduced the infarct size by a comparable degree (from 38 to 48 percent). Thiemermann et al., "Inhibition of the Activity of Poly (ADP Ribose) Synthetase Reduces Ischemia-Reperfusion Injury in the Heart and Skeletal Muscle", Proc. Nati Acad. Sci. USA, 94: 679-83 (1997). This discovery has suggested that PARP inhibitors may be able to save the heart or previously ischemic skeletal muscle tissue. It has also been shown that PARP activation provides an index of damage following neurotoxic aggressions with glutamate (by means of NMDA receptor stimulation), reactive oxygen intermediates, β-amyloid protein, normal methyl-4-phenyl- 1, 2, 3, 6-tetrahydropyridine (MPTP) and its active metabolite N-methyl-4-phenylpyridine (MPP +), which participate in pathological conditions, such as embolism, Alzheimer's disease and Parkinson's disease. Zhan et al., "Poly (ADP-Ribose) Synthetase Activation: An Early Indicator of Neurotoxic DNA Damage", J. Neurochem. , 65: 3, 1411-14 (1995). Other studies have continued to explore the role of PARP activation in cerebellar granule cells in vi tro, and in MPTP neurotoxicity. Cosi et al., "Poly (ADP-Ribose) Polymerase (PARP) Revisited A New Role for an Old Enzyme: PARP Involvement in Neurodegeneration and PARP Inhibitors as Possible Neuroprotective Agents," Ann. N. Y. Acad. Sci. , 825: 366-79 (1997); and Cosi et al., "Poly (ADP-Ribose) Polymerase Inhibitors Protect Against MPTP-induced Depletions of Striatal Dopamine and Cortical Noradrenaline in C57B1 / 6 Mice", Brain Res. , 729: 264-69 (1996). It is thought that neural damage following embolism and other neurodegenerative processes results from a massive release of the excitatory neurotransmitter glutamate, which acts on the N-methyl-D-aspartate (NMDA) receptors and other subtype receptors. Glutamate serves as the predominant excitatory neurotransmitter in the central nervous system (CNS). Neurons release glutamate in large quantities when deprived of oxygen, as may occur during an ischemic insult to the brain, such as an embolism, or a heart attack. This excess of glutamate release, in turn, causes an over-stimulation (excitotoxicity) of the N-methyl-D-aspartate (NMDA), AMPA, Kainate and MGR receptors. When glutamate is fixed to these receptors, the ion channels of the receptors are opened, allowing ion fluxes through their cell membranes, for example Ca and Na + into the cells, and K + out of the cells. These ion fluxes, especially the influx of Ca, cause an over-stimulation of the neurons. The over-stimulated neurons secrete more glutamate, creating a feedback loop or domino effect, which ultimately results in cellular damage or death by the production of proteases, lipases, and free radicals. Excessive activation of glutamate receptors has been implicated in different diseases and neurological conditions, including epilepsy, embolism, Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis (ALS), Huntington's disease, schizophrenia, chronic pain, ischemia and loss. neuronal followed by hypoxia, hypoglycemia, ischemia, trauma, and nerve aggression. Recent studies have also anticipated a glutamatergic base for compulsive disorders, particularly drug dependence. The evidence includes findings in many animal species, as well as brain cortical cultures treated with glutamate or NMDA, that glutamate receptor antagonists block neural damage following vascular attack. Dawson et al., "Protection of the Brain from Ischemia," Cerebrovascular Disease, 319-25 (H. Hunt Batjer ed., 1997). Attempts to prevent excitotoxicity by blocking the NMDA, AMPA, Kainate and MGR receptors have been difficult, because each receptor has multiple sites on which glutamate can be fixed. Many of the compositions that are effective in blocking receptors are also toxic to animals. As such, there is no known effective treatment for glutamate abnormalities. In turn, the stimulation of NMDA receptors activates the neuronal nitric oxide synthase enzyme (NNOS), which causes the formation of nitric oxide (NO), which mediates neurotoxicity more directly. There has been protection against NMDA neurotoxicity following treatment with NOS inhibitors. See Dawson et al., "Nitric Oxide Mediates Glutamate Neurotoxicity in Primary Cortical Cultures," Proc. Na ti. Acad. Sci. USA, 88: 6368-71 (1991); and Dawson et al., "Mechanisms of Nitric Oxide-mediated Neurotoxicity in Primary Brain Cultures," J. Neurosci. , 13: 6, 2651-61 (1993). Protection against NMDA neurotoxicity may also occur in cortical cultures of mice with targeted NNOS alteration. See Dawson et al., "Resistance to Neurotoxicity in Cortical Cultures from Neuronal Nitric Oxide Synthase-Deficient Mice," J. "Neurosci., 16: 8, 2479-87 (1996) .Neural damage is known to be followed by vascular embolism. notoriously in animals treated with NOS inhibitors, or in mice with genetic alteration of NNOS Iadecola, "Bright and Dark Sides of Nitric Oxide in Ischemic Brain Injury", Trends Neurosci., 20: 3, 132-39 (1997); and Huang et al., "Effects of Cerebral Ischemia in Mice Deficient in Neuronal Nitric Oxide Synthase", Science, 265: 1883-85 (1994). See also, Beckman et al., "Pathological Implications of Nitric Oxide, Superoxide and Peroxynitrite Formation". , Biochem, Soc. Trans., 21: 330-34 (1993), either NO, or peroxynitrite, can cause DNA damage, which activates PARP, and additional support is provided for this in Szabó et al. "DNA Strand Beakage, Activation of Poly (ADP-Ribose) Synthetas e, and Cellular Energy Depletion are Involved in the Cytotoxicity in Macrophages and Smooth Muscle Cells Exposed to Peroxynitrite ", Proc. Na ti. Acad. Sci. USA, 93: 1753 -58 (1996). Zhan et al., U.S. Patent No. 5,587,384, issued December 24, 1996, describes the use of certain PARP inhibitors, such as benzamide and 1,5-dihydroxy-isoquinoline, to prevent NMDA-mediated neurotoxicity. , and consequently, treat embolism, Alzheimer's disease, Parkinson's disease, and Huntington's disease. However, it has now been discovered that Zhan et al. May have been in error in classifying neurotoxicity as an NMDA-mediated neurotoxicity. Rather, it may have been more appropriate to classify the neurotoxicity in vivo present as neurotoxicity by glutamate. See Zhang et al., "Nitric Oxide Activation of Poly (ADP-Ribose) Synthetase in Neurotoxicity", Science, 263- 687-89 (1994). See also, Cosi et al., "Poly (ADP-Ribose) Polymerase Inhibitors Protect Against MPTP-induced Depletions of Striatal Dopamine and Cortical Noradrenaline in C57B1 / 6 Mice", Brain Res. , 729: 264-69 (1996). It is also known that PARP inhibitors affect DNA repair in general. Cristovao et al., "Effect of a Poly (ADP-Ribose) Polymerase Inhibitor on DNA Breakage and Cytotoxicity Induced by Hydrogen Peroxide and? -Radiation", Terato. , Carcino. , and Muta. , 16: 219-27 (1996), describe the effect of hydrogen peroxide and radiation-? on the breaks of DNA strands in the presence of, and in the absence of, 3-aminobenzamide, a potent PARP inhibitor. Cristovao and colleagues observed a PARP-dependent recovery of DNA strand breaks in leukocytes treated with hydrogen peroxide. PARP inhibitors have been reported to be effective in radiosensitizing hypoxic tumor cells, and are effective in preventing tumor cells from recovering from potentially lethal DNA damage after radiation therapy, presumably because of their ability to prevent DNA repair. . See Patents of the United States of North America Nos. 5,032,617; 5,215,738; and 5,041,653. There is also evidence that P-RP inhibitors are useful for the treatment of inflammatory bowel disorders. Salzman et al., "Role of Peroxynitrite and Poly (ADP-Ribose) Synthase Activation Experimental Colitis", Japanese J. Pharm. , 75, Supplement 1:15 (1997), describe the ability of PARP inhibitors to prevent or treat colitis. Colitis was induced in rats by intraluminal administration of the hapten trinitrobenzenesulfonic acid in 50 percent ethanol. The treated rats received 3-aminobenzamide, a specific inhibitor of PARP activity. Inhibition of PARP activity reduced the inflammatory response, and restored the morphology and energy status of the distal colon. See also, Southan et al., "Spontaneous Rearrangement of Aminoalkylithioureas into Mercaptoalkylguanidines, a Novel Class of Nitric Oxide Synthase Inhibitors with Selectivity Towards the Inducible Isoform," Br. J. Pharm. , 117.- 619-32 (1996); and Szabó et al., "Mercaptoethylguanidine and Guanidine Inhibitors of Nitric Oxide Synthase React with Peroxynitrite and Protect Against Peroxynitrite-induced Oxidative Damage", J. "Biol. Chem., 272: 9030 -36 (1997). PARP inhibitors are useful for treating arthritis Szabó et al, "Protective Effects of an Inhibitor of Poly (ADP-Ribose) Synthetase in Collagen-Induced Arthritis", Japanese J. Pharm., 75, Supplement 1: 102 (1997), describe the ability of PARP inhibitors to prevent or treat collagen-induced arthritis, see also Szabó et al, "DNA Strand Breakage, Activation of Poly (ADP-Ribose) Synthetase, and Cellular Energy Depletion are Involved in the Cytotoxicity in Macrophages. and Smooth Muscle Cells Exposed to Peroxynitrite, "Proc. Nati, Acad. Sci. USA, 93.-1753 -58 (March 1996), Bauer et al.," Modification of Growth Related Enzymatic Pathways and Apparent Loss of Tumo rigenicity of a ras-transformed Bovine Endothelial Cell Line by Treatment with 5-Iodo-6-amino-l, 2-benzopyrone (INH2BP) ", Intl. J. Oncol. , 8: 239-52 (1996); and Hughes et al., "Induction of T Helper Cell Hyporesponsiveness in an Experimental Model of Autoimmunity by Using Nonmitogenic Anti-CD3 Monoclonal Antibody", ". Immuno., 153: 3319-25 (1994). In addition, it appears that PARP inhibitors are useful for the treatment of diabetes Heller et al., "Inactiva ion de la Poly (ADP-Ribose) Polymerase Gene Affects Oxygen Radical and Nitric Oxide Toxicity in Islet Cells", J ". Biol. Chem., 270: 19, 11176-80 (May 1995), describe the tendency of PARP to deplete cellular NAD +, and induce the death of insulin-producing islet cells. Heller and colleagues used mice cells with inactivated PARP genes, and found that these mutant cells did not show NAD + depletion after being exposed to DNA damaging radicals. It was also found that the mutant cells are more resistant to NO toxicity. Still further, it has been shown that ß2 PARP inhibitors are useful for the treatment of endotoxic shock or septic shock. Zingarelli et al., "Protective Effects of Nicotinamide Against Nitric Oxide-Mediated Delayed Vascular Failure in Endotoxic Shock: Potential Involvement, of PolyADP Ribosyl Synthetase", Shock, 5: 258-64 (1996), suggest that inhibition of the repair cycle of the DNA triggered by poly (ADP ribose) synthetase has protective effects against vascular failure in endotoxic shock. Zingarelli et al. Found that nicotinamide protects against NO-mediated vascular failure delayed in endotoxic shock. Zingarelli and colleagues also found that the actions of nicotinamide may be related to the inhibition of NO-mediated activation of the energy-consuming DNA repair cycle triggered by poly (ADP-ribose) synthetase. See also, Cuzzocrea, "Role of Peroxynitrite and Activation of Poly (ADP-Ribose) Synthetase in the Vascular Failure Induced by Zymosan-activated Plasma", Bri t. J. Pharm. , 122: 493 -503 (1997). Yet another known use for PARP inhibitors is the treatment of cancer. Suto et al., "Dihydroisoquinolinones: The Design and Synthesis of a New Series of Potent Inhibitors of Poly (ADP-Ribose) Polymerase", Anticancer Drug Des. , 7: 107-17 (1991), disclose processes for synthesizing a number of different PARP inhibitors. In addition, Suto et al., U.S. Patent No. 5,177,075, describe various isoquinolines used to improve the lethal effects of ionizing radiation or chemotherapeutic substances on tumor cells. Weltin et al., "Effect of 6 (5H) -Phenanthridinone, an Inhibitor of Poly (ADP-ribose) Polymerase, on Cultured Tumor Cells", Oncol. Res. 6: 9, 399-403 (1994), describe the inhibition of PARP activity, the reduced proliferation of tumor cells, and a remarkable synergistic effect when the tumor cells are co-treated with an alkylating agent. Still another use for PARP inhibitors is the treatment of peripheral nerve lesions, and the resulting pathological pain syndrome known as neuropathic pain, such as that induced by chronic constriction injury (CCI) of the common sciatic nerve, and wherein transináptica alteration of the dorsal horn of the spinal cord characterized by hyperchromatosis of the cytoplasm and the nucleoplasm (called "dark" neurons). See Mao et al., Pain, 72: 355-366 (1997). PARP inhibitors have also been used to prolong the life and proliferative capacity of cells, including the treatment of diseases such as skin aging, Alzheimer's disease, atherosclerosis, osteoarthritis, osteoporosis, muscular dystrophy, skeletal muscle degenerative diseases. that involve replicative senescence, age-related macular degeneration, immune senescence, AIDS, and other immune senescence diseases; and to alter the genetic expression of senescent cells. See International Publication Number WO 98/27975. Large numbers of known PARP inhibitors have been described in Banasik et al., "Specific Inhibitors of Poly (ADP-Ribose) Synthetase and Mono (ADP-Ribosyl) -Transferase", J ". Biol. Chem., 267: 3, 1569 - 75 (1992), and in Banasik et al., "Inhibitors and Activators of ADP-Ribosylation Reactions", Molec. Cell. Biochem., 138: 185-97 (1994) .However, the approach of using these PARP inhibitors. in the manners described above, it has been limited in effect For example, side effects have been observed with some of the best-known PARP inhibitors, as described in Milam et al.

"Inhibitors of Poly (Adenosine Diphosphate-Ribose) Synthesis: Effect on Other Metabolic Processes ", Science, 223: 589 -91 (1984) . Specifically, the inhibitors of PARP 3-aminobenzamide and benzamide not only inhibited the action of PARP, but were also shown to affect cell viability, glucose metabolism, and DNA synthesis. Therefore, it was concluded that the utility of these PARP inhibitors can be severely restricted by the difficulty to find a dose that inhibits the enzyme without producing additional metabolic effects. SUMMARY OF THE INVENTION The present invention relates to a compound that inhibits the activity of PARP, and affects a neuronal activity not mediated by NMDA toxicity. Additionally, the present invention relates to a pharmaceutical composition comprising: (i) an effective amount of a compound that inhibits PARP activity, and affects a neuronal activity not mediated by NMDA toxicity; and (ii) a pharmaceutically acceptable carrier. The present invention further relates to compositions and methods for treating and / or preventing tissue damage resulting from cell damage or death due to necrosis or apoptosis, and associated diseases and conditions. Moreover, the present invention relates to a method for affecting a neuronal activity not mediated by toxicity by NMDA in an animal, which comprises administering to the animal an effective amount of a compound that inhibits PARP activity. The present invention also relates to a method for the treatment of a cardiovascular disorder in an animal, which comprises administering to the animal an effective amount of a compound that inhibits PARP activity and affects a neuronal activity not mediated by NMDA toxicity. .

. The present invention also relates to a method for the treatment of organ damage due to transplantation in an animal, which comprises administering to the animal an effective amount of a compound that inhibits PARP activity and affects a neuronal activity not mediated by the NMDA toxicity. The present invention further relates to a method for the treatment of an inflammatory bowel disorder in an animal, which comprises administering to the animal an effective amount of a compound that inhibits PARP activity and affects a neuronal activity not mediated by toxicity. by NMDA. Moreover, the present invention relates to a method for the treatment of arthritis in an animal, which comprises administering to the animal an effective amount of a compound that inhibits PARP activity and affects a neuronal activity not mediated by NMDA toxicity. . The present invention also relates to a method for the treatment of diabetes in an animal, which comprises administering to the animal an effective amount of a compound that inhibits PARP activity and affects a neuronal activity not mediated by NMDA toxicity. Additionally, the present invention relates to a method for the treatment of septic shock in an animal, which comprises administering to the animal an effective amount of a compound that inhibits PARP activity and affects a neuronal activity not mediated by NMDA toxicity. . The present invention further relates to a method for the treatment of cancer in an animal, which comprises administering to the animal an effective amount of a compound that inhibits PARP activity and affects a neuronal activity not mediated by NMDA toxicity. The present invention further relates to methods for radiosensitizing hypoxic tumor cells, which comprise administering an effective amount of a compound that inhibits PARP activity and that radiosensitizes tumor cells. The present invention also relates to methods for prolonging the life and proliferative capacity of cells, which comprise administering an effective amount of a compound that inhibits PARP activity. The present invention also relates to methods for altering the gene expression of senescent cells, which comprise administering an effective amount of a compound that inhibits PARP activity. The present invention further relates to a method for inhibiting PARP activity in an animal, which comprises administering to the animal an effective amount of a compound that inhibits PARP activity and affects a neuronal activity not mediated by NMDA toxicity.

Finally, the present invention relates to methods for administering an effective amount of a compound for the purpose of treating tissue damage resulting from cell damage or death due to necrosis or apoptosis, neural tissue damage resulting from ischemia and reperfusion injury or neurological disorders, and neurodegenerative diseases; to prevent or treat vascular embolism, to treat or prevent cardiovascular disorders; to treat other conditions and / or disorders, such as age-related macular degeneration, AIDS, and other immune senescence diseases, arthritis, atherosclerosis, cachexia, cancer, skeletal muscle degenerative diseases involving replicative senescence, diabetes, trauma of the head, immune senescence, inflammatory bowel disorders (such as colitis and Crohn's disease), muscular dystrophy, osteoarthritis, osteoporosis, chronic and / or acute pain (such as neuropathic pain), renal failure, retinal ischemia, septic shock (such as endotoxic shock), and aging of the skin; to prolong the life and the proliferative capacity of the cells; to alter the genetic expression of senescent cells; or to radiosensitize hypoxic tumor cells. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows the distribution of the infarction cross-sectional area at representative levels along the rostrocaudal axis, measured from the interaural line in the untreated animals and in the animals treated with 10 milligrams / kilogram of 3 , 4-dihydro-5- [4- (1-piperidinyl) -butoxy] -1 (2H) -isoquinolinone. Figure 2 shows the effect of the intraperitoneal administration of 3,4-dihydro-5- [4- (1-piperidinyl) -butoxy) -1 (2H) -isoquinolinone on the infarct volume. DETAILED DESCRIPTION OF THE INVENTION The compounds of the present invention preferably inhibit the activity of PARP, and act to treat or prevent neural tissue damage resulting from cell damage or cell death by necrosis or apoptosis. As such, they can treat or prevent neural tissue damage resulting from cell damage or cell death by necrosis or apoptosis, cerebral ischemia and reperfusion injury or neurodegenerative diseases in an animal; they can prolong the life and the proliferative capacity of the cells and, therefore, can be used to treat or prevent diseases associated with the same; can alter the genetic expression of senescent cells; and can radiosensitize hypoxic tumor cells. Preferably, the compounds of the invention treat or prevent tissue damage resulting from damage or cell death due to necrosis or apoptosis, and / or affect neuronal activity, whether mediated or not mediated, by NMDA toxicity. It is thought that these compounds interfere with more than neurotoxicity by glutamate and biological pathways mediated by NO. In addition, the compounds of the invention can treat or prevent other tissue damage related to the activation of PARP. For example, the compounds of the invention can treat or prevent damage to cardiovascular tissue resulting from cardiac ischemia or reperfusion injury. For example, reperfusion injury occurs at the end of cardiac bypass procedures, or during cardiac arrest when the heart, once prevented from receiving blood, begins to reperfuse. The compounds of the present invention can also be used to prolong or increase the life or proliferation of the cells, and therefore, to treat or prevent diseases associated therewith, and induced or exacerbated by cellular senescence, including aging of the cells. skin, atherosclerosis, osteoarthritis, osteoporosis, muscular dystrophy, skeletal muscle degenerative diseases involving replicative senescence, age-related macular degeneration, immune senescence, AIDS and other immune senescence diseases, and other diseases associated with cellular senescence and aging, as well as to alter the genetic expression of senescent cells. These compounds can also be used to treat cancer, and to radiosensitize hypoxic tumor cells, in order to make tumor cells more susceptible to radiation therapy, and to prevent tumor cells from recovering from potentially lethal damage. of DNA after radiation therapy, presumably because of its ability to prevent DNA repair. The compounds of the present invention can be used to prevent or treat vascular embolism, to treat or prevent cardiovascular disorders; to treat other conditions and / or disorders, such as age-related macular degeneration, AIDS, and other immune senescence diseases, arthritis, atherosclerosis, cachexia, cancer, skeletal muscle degenerative diseases involving replicative senescence, diabetes, trauma of the head, immune senescence, inflammatory bowel disorders (such as colitis and Crohn's disease), muscular dystrophy, osteoarthritis, osteoporosis, chronic and / or acute pain (such as neuropathic pain), renal failure, retinal ischemia, septic shock (such as endotoxic shock), and aging of the skin. Preferably, the compounds of the invention act as inhibitors of PARP, to treat or prevent tissue damage resulting from cell death or damage due to necrosis or apoptosis; to treat or prevent neural tissue damage resulting from cerebral ischemia and reperfusion injury or neurodegenerative diseases in an animal; to prolong and increase the life and proliferative capacity of cells; to alter the genetic expression of senescent cells; and to radiosensitize the tumor cells. It is thought that these compounds interfere with more than NMDA neurotoxicity and biological pathways mediated by NO. Preferably, the compounds of the invention exhibit an IC50 to inhibit PARP in vitro of about 100 μM or lower, more preferably, about 25 μM or lower. "Inhibition", in the context of enzymes, refers to a reversible enzymatic inhibition, such as competitive, uncompetitive and non-competitive inhibition. Competitive, uncompetitive, and noncompetitive inhibition can be distinguished by the effects of an inhibitor on the reaction kinetics of an enzyme. Competitive inhibition occurs when the inhibitor reversibly combines with the enzyme, such that it competes with a normal substrate to bind to the active site. The affinity between the inhibitor and the enzyme can be measured by the inhibitor constant, K-, which is defined as: [E] [I] K, = [The] where [E] is the concentration of the enzyme, [I] is the concentration of the inhibitor, and [El] is the concentration of the enzyme-inhibitor complex formed by the reaction of the enzyme with the inhibitor. Unless otherwise specified, K, -, as used herein, refers to the affinity between the compounds of the invention and PARP. "IC50" is a related term used to define the concentration or amount of a compound that is required to cause a 50 percent inhibition of the target enzyme. The inventors have now discovered that the selected compounds can inhibit PARP activity, and can ameliorate damage to neural tissue, including that followed by focal ischemia and reperfusion injury. In general, the inhibition of PARP activity prevents the cell from losing energy, preventing an irreversible depolarization of neurons, and therefore, provides neuroprotection. Although we do not want to be forced by the same, it is thought that the activation of PARP may have a common role in still other excitotoxic mechanisms, perhaps not yet discovered, in addition to the production of free radicals and NO. The present invention relates to compounds that inhibit PARP activity, and affect a neuronal activity not mediated by NMDA toxicity. Neuronal activity can be selected from the group consisting of the stimulation of damaged neurons, the promotion of neuronal regeneration, the prevention of neurodegeneration, and the treatment of a neurological disorder. Preferably, the neurological disorder is selected from the group consisting of peripheral neuropathy caused by physical injury or disease state, traumatic brain injury, physical damage to the spinal cord, embolism, demyelination disease and neurological disorder related to neurodegeneration. A preferred neurological disorder is embolism, and a preferred neurological disorder related to neurodegeneration is selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. The compound of the invention can interact with PARP by forming at least one hydrogen bond with an amino acid in the PARP, potentially Ser and / or Gly. Specifically, an NH group of the compound of the invention can form a hydrogen bond with the O-atom of Gly in the PARP. The length of this link is from about 1 to 5 A, preferably from about 2 to 4 A. Additionally, an O, S, or N atom of the compound of the invention can form a hydrogen bond with the H atom of Ser. The length of this bond is from about 1 to 5 Á, preferably from about 2 to 4. TO. Preferably, the compound of the invention exhibits an IC? - to inhibit PARP in about 100 μM or lower, more preferably about 25 μM or lower.

The compounds of the present invention possess one or more asymmetric centers, and can therefore be produced as mixtures (racemic and non-racemic) of stereoisomers, or as individual R- and S-stereoisomers. Individual stereoisomers can be obtained by using an optically active starting material, resolving a racemic or non-racemic mixture of an intermediate at some appropriate stage of the synthesis, or solving the compounds of the invention. It is understood that the compounds of the present invention encompass the individual stereoisomers, as well as mixtures (racemic and non-racemic) of stereoisomers. The term "isomers" refers to compounds having the same number and class of atoms, and therefore, the same molecular weight, but which differ with respect to the arrangement or configuration of the atoms. "Stereoisomers" are the isomers that differ only in the configuration of the atoms in space. "Enantiomers" are a pair of stereoisomers that are mirror images that can not be superimposed on one another. "Diastereoisomers" are stereoisomers that are not mirror images of one another. "Racemic mixture" means a mixture containing equal or regularly equal parts of the individual enantiomers. A "non-racemic mixture" is a mixture containing unequal, or substantially unequal, portions of the individual enantiomers or stereoisomers.

The compounds of the invention may be useful in a free base form, in the form of pharmaceutically acceptable salts, pharmaceutically acceptable hydrates, pharmaceutically acceptable esters, pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable metabolites, and in the form of pharmaceutically stereoisomers. acceptable These forms are all within the scope of the invention. In practice, the use of these forms adds to the use of the neutral compound. "Pharmaceutically acceptable salt", "hydrate", "ester" or "solvate", refer to a salt, hydrate, ester, or solvate of the compounds of the invention, which possess the desired pharmacological activity, and which are not biologically or otherwise undesirable. Organic acids can be used to produce salts, hydrates, esters or solvates, such as acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, p-toluenesulfonate, bisulfate, sulfamate, sulfate, naphthylate, butyrate, citrate, camphorrate, camphorsulfonate, cyclopentanpropionate. , digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glycoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, 2-hydroxyethane sulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, tosylate and undecanoate. Inorganic acids can be used to produce salts, hydrates, esters or solvates, such as hydrochloride, hydrobromide, iodide, and thiocyanate. Examples of suitable basic salts, hydrates, esters, or solvates include ammonia hydroxides, carbonates and bicarbonates, alkali metal salts, such as sodium, lithium and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts. , aluminum salts, and zinc salts. Salts, hydrates, esters or solvates with organic bases can also be formed. Organic bases suitable for the formation of pharmaceutically acceptable salts, hydrates, esters or base solvates of the compounds of the present invention include those which are non-toxic and which are strong enough to form such salts, hydrates, esters or solvates. For purposes of illustration, the class of such organic bases may include mono-, di-, and tri-alkylamines, such as methylamine, dimethylamine, triethylamine, and dicyclohexylamine; mono-, di-, or tri-hydroxyalkylamines, such as mono-, di-, and tri-ethanolamine; amino acids, such as arginine and lysine; guanidine; N-methylglucosamine; N-methylglucamine; L-glutamine; N-me t ilpipiperaz ina; morpholine; ethylenediamine; N-benzylphenethylamine; (trihydroxymethyl) aminoethane; and similar. See, for example, "Pharmaceutical Salts", J ". Pharm. Sci., 66: 1, 1-19 (1997) In accordance with the above, groups containing basic nitrogen can be quaternized with substances including: halides lower alkyl, such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl, and diamyl sulfates; long chain halides, such as chlorides, bromides, and iodides; decyl, lauryl, myristyl and stearyl, and aralkyl halides, such as benzyl and phenethyl bromides The salts, hydrates, esters, or solvates of acid addition of the basic compounds can be prepared either by dissolving the base free of a PARP inhibitor in an aqueous or aqueous alcohol solution, or in another suitable solvent containing the appropriate acid or base, and the isolation of the salt by evaporation of the solution. PA inhibitor RP can be reacted with an acid, as well as reacting the PARP inhibitor having an acidic group thereon, with a base, such that the reactions are in an organic solvent, in which case, the salt separate directly, or can be obtained by concentrating the solution. "Pharmaceutically acceptable prodrug" refers to a derivative of the compounds of the invention, which undergoes biotransformation before exhibiting its pharmacological effects. The prodrug is formulated with the aim of having a better chemical stability, a better acceptance and compliance of the patient, a better bioavailability, a prolonged duration of action, a better organ selectivity, a better formulation (e.g., a greater water solubility). ), and / or reduced side effects (eg, toxicity). The prodrug can be easily prepared from the compounds of the invention, using methods known in the art, such as those described by Burger's Medicinal Chemistry and Drug Chemistry, Fifth Edition, Volume 1, pages 172-178, 949-982 (nineteen ninety five) . For example, the compounds of the invention can be transformed into prodrugs by the conversion of one or more of the hydroxyl or carboxyl groups, into esters. "Pharmaceutically acceptable metabolite" refers to drugs that have undergone a metabolic transformation. After entering the body, most drugs are substrates for chemical reactions that can change their physical properties and their biological effects. These metabolic conversions, which normally affect the polarity of the compound, alter the way in which drugs are distributed in, and are excreted from, the body. However, in some cases, the metabolism of a drug is required for a therapeutic effect. For example, cancer drugs of the antimetabolite class must be converted to their active forms after they have been transported into a cancer cell. Because most drugs undergo metabolic transformation of some kind, the biochemical reactions that play a role in the metabolism of the drug can be numerous and diverse. The main site of drug metabolism is the liver, although other tissues can also participate. A feature of many of these transformations is that metabolic products are more polar than parental drugs, although a polar drug sometimes produces a less polar product. Substances with high lipid / water partition coefficients, which easily pass through the membranes, also diffuse back easily from the tubular urine through the renal tubular cells to the plasma. Therefore, these substances tend to have a low renal release and a long persistence in the body. If a drug is metabolized to a more polar compound, one with a lower division coefficient, its tubular reabsorption will be greatly reduced. Moreover, the specific secretory mechanisms for anions and cations in the proximal renal tubules and in the parenchymal liver cells operate on highly polar substances. As a specific example, phenacetin (acetofenetidine) and acetanilide are both light analgesic and antipyretic substances, but are transformed inside the body to a more polar and more effective metabolite, p-hydroxyacetanilide (acetaminophen), which is widely used in the present. When a dose of acetanilide is given to a person, the successive metabolites reach a peak and decay in the plasma in sequence. During the first hour, acetanilide is the main component of the plasma. In the second hour, as the level of acetanilide decreases, the concentration of the metabolite acetaminophen reaches a peak. Finally, after a few hours, the main component of the plasma is an additional metabolite that is inert and can be excreted from the body. Accordingly, the plasma concentrations of one or more metabolites, as well as the drug itself, can be pharmacologically important. The reactions involved in drug metabolism are often classified into two groups, as shown in Table II. Phase I is functionalization reactions, and generally consists of: (1) oxidation and reduction reactions that alter and create new functional groups, and (2) hydrolytic reactions that dissociate the esters and amides to release masked functional groups. These changes are usually in the direction of the greatest polarity. Phase II reactions are conjugation reactions in which the drug, or often a metabolite of the drug, is coupled to an endogenous substrate, such as glucuronic acid, acetic acid or sulfuric acid. TABLE II Reactions of Phase I (functionalization reactions); (1) Oxidation by means of the hepatic microsomal system Aliphatic oxidation Aromatic hydroxylation N-Desalkylation O-Desalkylation S-Desalkylation Epoxidation Oxidative deamination Sulfoxide formation Desulfurization N-oxidation and N-hydroxylation Dehalogenation (2) Oxidation by non-microsomal mechanisms: Oxidation with alcohol and aldehyde Oxidation with purine Oxidative deamination (monoamine oxidase and diamine oxidase). (3) Reduction: Reduction with azo and nitro (4) Hydrolysis: Ester and amide hydrolysis Peptide bond hydrolysis Epoxide hydration Phase II reactions (conjugation reactions); '1) Glucuronidation (2) Acetylation (3) Formation of mercapturic acid (4) Conjugation of sulfate (5) N-, O-, and S-methylation (6) Trans-sulfidation Synthesis of the Compounds Many PARP inhibitors can be synthesized by known methods from starting materials that are known, which are themselves commercially available, or can be prepared by the methods used to prepare the corresponding compounds in the literature. See, for example, Suto et al., "Dihydroisoquinolinones: The Design and Synthesis of a New Series of Potent Inhibitors of Poly (ADP-ribose) Polymerase", Anticancer Drug Des., 6: 107-17 (1991), which give Understand processes to synthesize a number of different PARP inhibitors. The following are synthesis methods for differently substituted multicyclic nitrogen-containing PARP inhibitors that affect neuronal activity not mediated by NMDA toxicity, including carboxamide compounds, thioalkyl compounds, alkoxy-substituted compounds, compounds substituted by amino, oxo-substituted compounds, and selected tricyclic compounds.

Synthesis of Carboxamide PARP Inhibitors A process for the preparation of a PARP inhibitor of example carboxamide, 5-carbamoylquinoline-4-carboxylic acid is described below: A mixture of m-cyanoaniline (1.0 grams, 8.46 millimoles) and diethyletoxylene malonate (1.97 grams, 9.13 millimoles) was stirred at 100 ° C-110 ° C for 1 hour, to form a homogeneous solution. The solution was cooled to room temperature, and pale yellowish crystals formed. The crystals were collected and washed with hexane, yielding 2.33 grams (100 percent yield) of a-carbetoxy- / 3- (m-cyanoanilino) ethyl acrylate (1), m.p. 109-111 ° C. The acrylate ester (1) was added through the top of a portioned air condenser to the boiling diphenyl ether (10 milliliters). After a few minutes of addition, crystals formed. The resulting mixture was heated at the same temperature for 30 minutes, and then cooled to room temperature. The crystals were collected and washed with hexane, to give 1.79 grams of the esters of the regioisomer (2) (yield of 89.5 percent), m.p. 305-307 ° C (decomposition). The esters (2) (179. grams, 7.39 mmol) were suspended in 10 percent NaOH (15 milliliters), and the mixture was heated to reflux for 1 hour, and cooled. Decolorizing charcoal (1.0 gram) was added, and the mixture was heated to reflux for an additional 10 minutes. The solid was removed, and the filtrate was acidified to a pH of 5 with 10 percent HCl. A cream precipitate was collected, washed with water and hexane, and dried to give the mixtures of acid isomers (3), 1.63 grams (100 percent yield), m.p. > 320 ° C. The acids (3) (0.5 grams, 2.33 millimoles) were added to the previously heated polyphosphoric acid (PPA) (2.2 grams) in portions over a period of about 8 minutes with agitation at 255 ° C-265 ° C. The mixture was heated at the same temperature for 20 minutes, cooled to room temperature, and then poured into ice water. An unwanted precipitate, 0.259 grams of 7-aminocarbonyl-4-hydroxy-isoquinoline was formed, collected and washed with water (59.1 percent yield). The remaining aqueous solution was adjusted to a pH of 5 to 6 with a solution of NaHCO 3 to precipitate 138 milligrams of 4-hydroxyquinoline-5-carboxamide (4) (yield of 31.5 percent), m.p. > 250ßC. Compound (4) (1.0 gram, 5.88 mmol) was suspended in P? Cl3, and the resulting mixture was heated to a temperature of 130 ° C (bath temperature). After 10 minutes, the suspension became a dark solution, and the gases were released vigorously. After 1 hour and 45 minutes, the reaction was completed, as shown by thin layer chromatography. The reaction mixture was cooled to room temperature, poured into ice water, and basified with 10 percent NaOH to a pH of 9. A pale purple precipitate formed, was collected and washed with water. The solid was dissolved in MeOH, and decolorized with activated carbon. The solid was removed, and the remaining filtrate was evaporated in vacuo to provide 300 milligrams (25 percent yield) of a white crystalline powder, 4-hydroxyquinoline-5-carboxamide (5), m.p. 205-207 ° C. Normal butyl lithium (3.88 mmol) in hexane was slowly added to a solution of 4-hydroxyquinoline-5-carboxamide (5) (400 milligrams, 1.94 mmol) in tetrahydrofuran (10 milliliters), at a temperature of -78 ° C. Next, dry C02 gas was bubbled into the mixture for 15 minutes at -78 ° C. A saturated solution of NH4C1 (20 milliliters) was also added. The mixture was warmed to room temperature, concentrated, and the remaining residue was dissolved in a saturated solution of Na 2 CO 3. The resulting aqueous solution was washed with ether, and then acidified to a pH of 6 with 1N HCl, to provide 124 milligrams of the product compound (6) as a solid. Additionally, compounds related to 8-carboxy-naphthalene-1-carboxamide (also known as 8-carbamoyl-naphthalene-carboxylic acid) can be prepared, shown below: by known chemical syntheses, such as, for example, that described in Gazz. Chim. I such. 79: 603-605 (1949). Moreover, the particular compound shown above is commercially available from Lancaster Synthesis Inc., P.O. Box 1000, Windham, NH 03087, USA. Synthesis of Thioalkyl PARP Inhibitors The usual building blocks for synthesizing organosulfur compounds are alkyl thiols, sometimes called mercaptans, which can be handled in a manner very similar to alcohols. Specifically, PARP inhibitors of thioalkyl compound can be prepared through nucleophilic or radical reactions, such as: alkyl-SH + Although direct nucleophilic displacements are not normally present on the simple aryl halides, the reaction to form a thioalkyl compound proceeds easily, for example: alkyl- SCu + g alkyl Another synthetic path is to form a cyclic thiol, and then use the addition of free radicals from an alkene to the thiol to form a thioalkyl PARP inhibitor, as shown below: rent The thioalkyls themselves can be prepared easily by the action of sulfur on Grignard reagents, or by the hydrolysis of the thioalkyl esters, shown below: ArMgBr AsRMgBr H20 + ArSH ether 0 Alkyl-SCCHg l.OH Alkyl-SH 2. H30 Example of a thioalkyl PARP inhibitor comprises the following steps: Kz re The Synthesis of PARP Inhibitors Substituted by Alcoxyl The PARP inhibitors substituted by alkoxyl can be prepared by reacting an alkoxide with a primary alkyl halide, to give an ether, through a SN2 path, a process known as the synthesis of ether of Williamson. Specifically, an alkoxide anion is reacted with RX, wherein X is bromine, chlorine, or iodine. The necessary alkoxide anion to process the Williamson reaction is usually generated by the reaction of an alcohol with a strong base, such as sodium hydride, NaOH, KOH, K2C03, Na2CO, normal butyl lithium, or the like. The resulting acid-base reaction produces the intermediate anion for the reaction with the RX halide. Specific examples of this reaction include: Typically, the reactions shown above take place in a solvent which is inert with respect to both the alkoxide anion and RX, and which allows at least some of the RX's to enter solution. Typical solvents include, for example, methylene chloride, chloroform, tetrahydrofuran, dimethyl formamide, and a variety of other inert organic solvents. The reaction described above can take place at different temperatures, depending, for example, on the solvent used, on the solubility of the alkoxide anion and on the RX in the solvent that is being used, and on the susceptibility of the reactions to oxidation or to participate in secondary reactions. Preferably, however, when the above reaction is used, it takes place at a temperature from about 0 ° C to about 100 ° C, preferably at about room temperature. The time required for the above reaction can also vary widely, depending on very similar factors. Normally, however, the reaction takes place within a time from about 5 minutes to about 24 hours, preferably from about 10 minutes to about 2 hours. The sequence of alcohol addition, the base, a solvent (if used), and the compound RX, can vary in a significant way, depending on the relative reactivities of these materials, the purity of these materials, the temperature at which the reaction takes place, the degree of agitation used in the reaction, and the like. However, preferably, the alkoxide anion intermediate is first dissolved in a solvent, the base is added, and then the compound RX is added. Synthesis of PARP Inhibitors Substituted by Amino Some of the many general methods used to prepare amines are: (1) reduction of the corresponding nitro compounds, especially to produce aromatic amines; (2) reaction of halides with ammonia and amines, especially wherein the halide is an alkyl group or an aryl group having electron withdrawing substituents; (3) reductive amination of the corresponding ketone to form primary, secondary, or tertiary amines, as shown below: \ \ C = O NH3 H Ni, c CH-NH2 / - Ni > . \ RNH2 H2 CH-NHR / Ni "\ R? NH H2 CH-NR2 / The above reactions usually occur in the presence of methanol or ethanol and a reducing agent, such as NaBH3CN. (4) Reduction of the corresponding nitriles, - and (5) Hoffman degradation of the amides, as shown below: RC0NH2 RNH2 + CO3 or KOBr A1-CONH2 ArNH2 + CO3 We next have a procedure for the preparation of a PARP inhibitor substituted by example amino: As indicated below, the last step in the above reaction can also be carried out with thionyl chloride (SoCl2) instead of phosphorus oxychloride (P0C13): Synthesis of Oxo-Substituted PARP Inhibitors Fenantridinones are the preferred building blocks for synthesizing multicyclic nitrogen-containing PARP inhibitors, which are replaced by double-linked oxygen. The Schmidt method can be used in a conventional manner to make genetically substituted (5H) -phenanthridin-6-one PARP inhibitors, as illustrated below: Fluoren-9 -one 5 (H) -fenantridin-6-one Phenanthridinones can also be prepared through an intramolecular Heck reaction analogous to that disclosed by Chide et al., Tetrahedron Lett. , 32:35, 4525-28 (1991). Other methods that may be useful in the preparation of oxo-substituted PARP inhibitors include, but are not limited to: I. the reaction of Smith, by Respondly et al., Acad. Sci. Paris, Ser. C, (1967); II. The photocyclization method described by Ninomiya et al., Tetrahedron Lett. , 4451 (1970) and Ichiya et al., J ". Chem. Soc., 1: 2257 (1973); III. Reactions of intramolecular cycloaddition of isocyanate, such as are found in: (a) Balazs et al., Synthesis, 1373 (nineteen ninety five); Banwell et al., J. Chem. Soc., 1: 3515 (1994); (b) Migachev et al., J. "Org. Chem. USSR (Eng. Trans.), 20: 8, 1565-71 1984) and Zh. Org. Khim., 20: 8, 1718-24 (1984); (c) Migachev et al., Chem. Heterocycl.

Compd. (Eng. Trans.), 17: 3, 289-94 (1981) and Khim. Geterotsikl.

Soedin , 17: 3, 388-91 (1981); (d) Migatschew et al., J ". Gen. Chem. USSR (Eng. Trans.); 48 2116, (1978); (e) Chandler et al., Aust. J. Chem., 20, 2037-44 (1967); (f) Ruediger et al., Can. J. Chem. 64-, 577-90 (1986). Synthesis of Tricyclic PARP Inhibitors A process for the preparation of a tricyclic nitrogen-containing PARP inhibitor, for example, 1H-benzo [de] iso-quinolin-1, 3 (2H) -dione R-substituted, is shown in followed: (1) (2) The starting R-substituted 1, 8-naphthalic anhydride can be purchased from commercial sources, or it can be known in the chemical literature and is accessible by processes known to one skilled in the art. To a solution of R-substituted 1,8-naphthalic anhydride (1) (10 mmol) in ethanol (100 milliliters), ammonia is introduced at a temperature of 40 ° C. After about 5 minutes, the ammonia gas line is removed, and the mixture is continuously stirred at 50 ° C for 2 hours. The ethanol solvent and the excess ammonia are removed in vacuo. The resulting residue is purified by crystallization, or by column chromatography on silica gel, to give the desired lH-benzo [de] isoquinoline-1, 3 (2H) -dione (2), which appears as essentially colorless crystals. Another procedure for the preparation of a tricyclic N-containing PARP inhibitor, for example, 2, 3, 3a, 9b-tetrahydro-1H-benzo [de] isoquinolin-1-one, is shown below: (1) (2) To a solution of sodium borohydride (5 mmol) in ethanol / water (20 milliliters, volume / volume: 10/1), is added lH-benzo [de] isoquinolin-1,3 (2H) -dione R- replaced (0.5 millimoles), obtained from Example 1 above. The resulting mixture is stirred for 4 hours at 60 ° C. After stopping the reaction with 2N hydrochloric acid, the reaction mixture is extracted with methylene chloride (30 milliliters x 3). The organic layers are combined and dried over anhydrous sodium sulfate. Then the solvent is removed, leaving a solid residue. The residue is purified by crystallization, or by column chromatography on silica gel, to give the desired compound, 2, 3, 3a, 9b-tetrahydro-1H-benzo [de] -isoquinolin-1-one (2), which appears as essentially colorless crystals. The following are some additional methods for the preparation of tricyclic nitrogen-containing PARP inhibitors, for example: 2. RMgX The products of each of the above syntheses for each type of PARP inhibitor are isolated from their respective reaction mixtures by conventional techniques, such as precipitation, extraction with an immiscible solvent under appropriate pH conditions, evaporation, filtration, crystallization, or by column chromatography on silica gel, and the like. However, normally the products are removed by crystallization or column chromatography on silica gel. Other variations and modifications of this invention using the synthetic routes described above will be obvious to those skilled in the art. The precursor compounds can be prepared by methods known in the art. See, for example, L. Paquette, Principies of Modern Heterocyclic Chemistry (1968). Typically, the PARP inhibitors used in the composition of the invention will have an IC50 to inhibit poly (ADP-ribose) polymerase in vitro of 100 μM or lower, preferably 25 μM or lower, more preferably 12 μM. or lower, and still more preferably 12 mM or lower. Pharmaceutical Compositions The present invention further relates to a pharmaceutical composition comprising: (i) an effective amount of a compound that inhibits PARP activity, treats tissue damage resulting from cell damage or death due to necrosis or apoptosis, or affects a neuronal activity not mediated by NMDA toxicity; and (ü) a pharmaceutically acceptable vehicle.

Neuronal activity can be selected from the group consisting of the stimulation of damaged neurons, the promotion of neuronal regeneration, the prevention of neurodegeneration, and the treatment of a neurological disorder. Preferably, the neurological disorder is selected from the group consisting of peripheral neuropathy caused by physical injury or disease state, traumatic brain injury, physical damage to the spinal cord, embolism, demyelination disease and neurological disorder related to neurodegeneration. A preferred neurological disorder is embolism, and a preferred neurological disorder related to neurodegeneration is selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. The compound of the pharmaceutical composition of the invention can interact with PARP by forming at least one hydrogen bond with an amino acid in the PARP, potentially Ser and / or Gly. Specifically, an NH group of the compound can form a hydrogen bond with the O-atom of Gly in the PARP. The length of this link is from about 1 to 5 A, preferably from about 2 to 4 A. Additionally, a 0, S, or N atom of the compound can form a hydrogen bond with the H atom of Ser. The length of this bond is from about 1 to 5 Á, preferably from about 2 to 4 A. In a further preferred embodiment of the invention, the compound of the composition exhibits an IC50 to inhibit PARP in about 100 μM or lower, more preferably about 25 μM or lower. A further embodiment encompasses the compounds described herein, compositions containing them, and methods of using them, including methods for inhibiting PARP activity by administration of a compound, as described above. In still further embodiments, the amount of the compound administered in the methods of the invention is sufficient to treat tissue damage resulting from cell damage or death due to necrosis or apoptosis, neural tissue damage resulting from ischemia and reperfusion injury or neurological disorders. , and neurodegenerative diseases; to prevent or treat vascular embolism, to treat or prevent cardiovascular disorders; to treat other conditions and / or disorders, such as age-related macular degeneration, AIDS, and other immune senescence diseases, arthritis, atherosclerosis, cachexia, cancer, skeletal muscle degenerative diseases involving replicative senescence, diabetes, head trauma, immune senescence, inflammatory disorders of the bowel (such as colitis and Crohn's disease), muscular dystrophy, osteoarthritis, osteoporosis, chronic and / or acute pain (such as neuropathic pain), kidney failure, retinal ischemia, septic shock (such as endotoxic shock), and aging of the skin; to prolong the life and the proliferative capacity of the cells; to alter the genetic expression of senescent cells; or to radiosensitize hypoxic tumor cells. In another preferred embodiment of the pharmaceutical composition of the invention, the compound is present in an amount that is effective to treat a cardiovascular disorder in an animal. The cardiovascular disorder can be selected from the group consisting of coronary artery disease, angina pectoris, myocardial infarction, cardiac arrest, cardiogenic shock, and cardiovascular tissue damage. In still another preferred embodiment of the pharmaceutical composition of the invention, the compound is present in an amount that is effective to treat organ damage due to transplantation. In a further preferred embodiment of the pharmaceutical composition of the invention, the compound is present in an amount that is effective to treat an inflammatory bowel disorder in an animal. Preferably, the inflammatory disorder of the intestine is Crohn's disease or colitis.

In still another preferred embodiment of the pharmaceutical composition of the invention, the compound is present in an amount that is effective to treat arthritis in an animal.

In a further preferred embodiment of the pharmaceutical composition of the invention, the compound is present in an amount that is effective to treat diabetes in an animal. In still another preferred embodiment of the pharmaceutical composition of the invention, the compound is present in an amount that is effective to treat septic shock in an animal. In another preferred embodiment, the type of septic shock is endotoxic shock or acute tubular necrosis. In yet another preferred embodiment of the present invention, the pharmaceutical composition contains the compound in an amount effective to treat tissue damage resulting from cell damage or death due to necrosis or apoptosis, and diseases and conditions related thereto, including, but not limited to, limited to, renal failure, cachexia, retinal ischemia, skin aging, atherosclerosis, osteoarthritis, osteoporosis, chronic pain, acute pain, neuropathic pain, muscular dystrophy, skeletal muscle degenerative diseases involving replicative senescence, macular degeneration related to age , immune senescence, AIDS and other diseases of immune senescence, and cancer. In the additional embodiments of the present invention, the compound in the pharmaceutical composition is present in amounts sufficient to prolong the life and proliferative capacity of the cells; and / or to alter the genetic expression of senescent cells; and / or to radiosensitize hypoxic tumor cells. Finally, in another preferred embodiment of the pharmaceutical composition of the invention, the compound is present in an amount that is effective to treat cancer in an animal. Cancer can be selected from the group consisting of tumors that produce ACTH, acute lymphocytic leukemia, acute non-lymphocytic leukemia, adrenal cortex cancer, bladder cancer, brain cancer, breast cancer, cervical cancer, lymphocytic leukemia chronic, chronic myelocytic leukemia, colorectal cancer, cutaneous T-cell lymphoma, endometrial cancer, esophageal cancer, Ewing sarcoma, gall bladder cancer, hairy cell leukemia, head and neck cancer, Hodgkin's lymphoma, Kaposi's sarcoma, cancer Kidney cancer, liver cancer, lung cancer (small and / or small cells), malignant peritoneal effusion, malignant pleural effusion, melanoma, mesothelioma, multiple myeloma, neuroblastoma, non-Hodgkin's lymphoma, osteosarcoma, ovarian cancer, ovarian cancer (germ cells), pancreatic cancer, cancer of the penis, prostate cancer, retinoblastoma, skin cancer, sarcoma of the tissue soft, squamous cell carcinomas, stomach cancer, testicular cancer, thyroid cancer, trophoblastic neoplasms, uterine cancer, vaginal cancer, cancer of the vulva and Wilm's tumor.

The compounds of the invention are useful in the manufacture of pharmaceutical formulations comprising an effective amount thereof in conjunction with, or as a mixture with, excipients or vehicles suitable for enteral or parenteral application. As such, the formulations of the present invention suitable for oral administration may be in the form of separate units, such as capsules, cachets, tablets, troches or lozenges, each containing a predetermined amount of the active ingredient; in the form of a powder or granules; in the form of a solution or suspension in an aqueous liquid or in a non-aqueous liquid; or in the form of an oil-in-water emulsion or a water-in-oil emulsion. The active ingredient may also be in the form of a bolus, electuary, or paste. Each formulation may contain from about 0.01 percent to about 99.99 percent by weight, preferably from about 3.5 percent to about 60 percent by weight of the compound of the invention, as well as one or more pharmaceutical excipients, such as wetting agents, emulsifiers, and pH regulators. The composition will normally be formulated in a unit dosage form, such as a tablet, capsule, suspension or aqueous solution. These formulations typically include a solid, semi-solid, or liquid vehicle. Exemplary carriers include lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia gum, calcium phosphate, mineral oil, cocoa butter, theobroma oil, alginates, tragacanth, gelatin, syrup, methylcellulose, sorbitan monolaurate, polyoxyethylene, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, corn starch, and the like. Particularly preferred formulations include gelatin capsules and tablets comprising the active ingredient together with (a) diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, dried corn starch, and glycine; and / or (b) lubricants, such as silica, talc, stearic acid, its magnesium or calcium salt, and polyethylene glycol. The tablets may also contain binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, and polyvinylpyrrolidone; disintegrants, such as starches, agar, alginic acid or its sodium salt, and effervescent mixtures; and / or absorbents, colorants, flavors, and sweeteners. The compositions of the invention may be sterilized and / or may contain auxiliaries, such as preservatives, stabilizers, fluidization agents, or emulsifiers, solution promoters, salts for regulating the osmotic pressure, and / or pH regulators. In addition, the composition may also contain other therapeutically valuable substances. The aqueous suspensions may contain emulsifying and suspending agents combined with the active ingredient. All oral dosage forms may also contain sweetening and / or flavoring and / or coloring agents. These compositions are prepared according to conventional mixing, granulating, or coating methods, respectively, and contain from about 0.1 to 75 percent of the active ingredient, preferably from about 1 to 50 percent thereof. A tablet can be made by compressing or molding the active ingredient, optionally with one or more auxiliary ingredients. Compressed tablets can be prepared by compression, in a suitable machine, of the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active substance, or dispersant. The molded tablets can be made by molding, in a suitable machine, a mixture of the active ingredient in powder and a suitable vehicle moistened with an inert liquid diluent.

When administered parenterally, the composition will normally be in a sterile injectable unit dosage form (isotonic aqueous solution, suspension or emulsion) with a pharmaceutically acceptable carrier. These vehicles are preferably non-toxic, parenterally acceptable, and contain diluents or non-therapeutic solvents. Examples of these vehicles include water; aqueous solutions, such as serum (isotonic sodium chloride solution), Ringer's solution, dextrose solution, and Hanks' solution; and non-aqueous vehicles, such as 1,3-butanediol, fixed oils (e.g., corn oil, cottonseed oil, peanut oil, sesame oil, and synthetic mono- or di-glyceride), ethyl oleate, and isopropyl myristate. Oleaginous suspensions may be formulated according to techniques known in the art, using suitable dispersing or wetting agents, and suspending substances. Among the acceptable solvents or suspending media are the sterile fixed oils. For this purpose, any soft fixed oil can be used. Also useful are fatty acids, such as oleic acid and its glyceride derivatives, including olive oil and castor oil, especially in its polyoxyethylated forms, in the preparation of injectables. These oily solutions or suspensions may also contain long chain alcohol diluents or dispersants. Sterile serum is a preferred vehicle, and the compounds are often sufficiently soluble in water to form as a solution for all foreseeable needs. The vehicle may contain minor amounts of additives, such as substances that improve solubility, isotonicity, and chemical stability, for example, antioxidants, regulators, and preservatives. When administered rectally, the composition will normally be formulated in a unit dosage form, such as a suppository or capsule. These compositions can be prepared by mixing the compound with suitable non-irritating excipients that are solid at room temperature, but liquid at the rectal temperature, such that they melt in the rectum to release the compound. Common excipients include cocoa butter, beeswax and polyethylene glycols or other fat emulsions or suspensions.

Moreover, the compounds can be administered topically, especially when the conditions directed for treatment involve easily accessible areas or organs by topical application, including neurological disorders of the eye, the skin or the lower intestinal tract.

For topical application to the eye, or for ophthalmic use, the compounds can be formulated as micronized suspensions in isotonic sterile serum with adjusted pH, or preferably, as a sterile isotonic serum solution with adjusted pH, either with or without a conservative, such as benzylalkonium chloride. In an alternative way, the compounds can be formulated into ointments, such as petrolatum. For topical application to the skin, the compounds may be formulated into suitable ointments containing the suspended or dissolved compounds in, for example, mixtures with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax, and water. Alternatively, the compounds can be formulated in suitable lotions or creams containing the active compound suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, polysorbate 60, wax cetyl ester, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. Topical application to the lower intestinal tract can be done in rectal suppository formulations (see above), or in suitable enema formulations. Formulations suitable for nasal or buccal administration (such as self-propelling powder dosage formulations), they may comprise from about 0.1 percent to about 5 weight percent / weight of the active ingredient, or, for example, about 1 weight percent / weight thereof. In addition, some formulations can be compounded in a sublingual troche or lozenge. The formulations may conveniently be presented in a unit dosage form, and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of placing the active ingredient in association with the vehicle that constitutes one or more auxiliary ingredients. In general, the formulations are prepared by placing the active ingredient in a uniform and intimate manner in association with a liquid carrier or a finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired formulation. In a preferred embodiment, the carrier is a biodegradable solid polymer, or a mixture of biodegradable polymers with appropriate release characteristics on time and release kinetics. The composition of the invention can then be molded into a suitable solid implant to provide effective concentrations of the compounds of the invention for a prolonged period of time, without the need for frequent redosing. The composition of the present invention can be incorporated into the biodegradable polymer or a mixture of polymers in a suitable manner known to those of ordinary skill in the art, and can form a homogenous matrix with the biodegradable polymer, or it can be encapsulated in some way inside the polymer, or it can be molded into a solid implant. In one embodiment, the biodegradable polymer or polymer mixture is used to form a soft "reservoir" containing the pharmaceutical composition of the present invention, which can be administered as a flowable liquid, for example, by injection, but which remains sufficiently viscous to maintain the pharmaceutical composition within the area located around the injection site. The degradation time of the deposit thus formed can vary from several days to a few years, depending on the selected polymer and its molecular weight. By using a polymeric composition in injectable form, the need to make an incision can even be eliminated. In any case, a flexible or flowable "reservoir" will adjust to the shape of the space it occupies inside the body with minimal trauma to the surrounding tissues. The pharmaceutical composition of the present invention is used in amounts that are therapeutically effective, and the amounts used may depend on the desired release profile, the concentration of the pharmaceutical composition required for the sensitizing effect, and the time it will be released. the pharmaceutical composition for the treatment.

The composition of the invention is preferably administered as a capsule or tablet containing a single dose or a series of divided doses of the compound, or as a solution, suspension, or sterile emulsion, for parenteral administration in a single dose or in divided doses. . In another preferred embodiment, the compounds of the invention can be prepared in a lyophilized form. In this case, 1 to 100 milligrams of a PARP inhibitor can be lyophilized in individual bottles, together with a vehicle and a pH regulator, such as mannitol and sodium phosphate. The composition can then be reconstituted in the bottles with bacteriostatic water before its administration. The compounds of the invention are used in the composition in amounts that are therapeutically effective. Although the effective amount of the PARP inhibitor will depend on the particular compound being used, amounts of these compounds ranging from about 1 percent to about 65 percent in liquid or solid carrier delivery systems have been readily incorporated. Methods of the Invention The present invention further relates to a method for treating or preventing tissue damage resulting from cell damage or death due to necrosis or apoptosis, and / or to a method for affecting a neuronal activity not mediated by NMDA toxicity in an animal, which comprises administering to the animal an effective amount of a compound that inhibits PARP activity. Neuronal activity can be selected from the group consisting of the stimulation of damaged neurons, the promotion of neuronal regeneration, the prevention of neurodegeneration, and the treatment of a neurological disorder. Preferably, the neurological disorder is selected from the group consisting of peripheral neuropathy caused by physical injury or disease state, traumatic brain injury, physical damage to the spinal cord, embolism, demyelination disease and neurological disorder related to neurodegeneration. A preferred neurological disorder is embolism, and the preferred neurological disorder related to neurodegeneration is selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. The present invention also relates to a method for the treatment of a cardiovascular disorder in an animal, which comprises administering to the animal an effective amount of a compound that inhibits PARP activity and affects a neuronal activity not mediated by NMDA toxicity. . The cardiovascular disorder can be selected from the group consisting of coronary artery disease, angina pectoris, myocardial infarction, cardiac arrest, cardiogenic shock, and damage to cardiovascular tissue. The present invention also relates to a method for the treatment of organ damage due to transplantation in an animal, which comprises administering to the animal an effective amount of a compound that inhibits PARP activity and affects a neuronal activity not mediated by the NMDA toxicity.

The present invention further relates to a method for the treatment of an inflammatory bowel disorder in an animal, which comprises administering to the animal an effective amount of a compound that inhibits PARP activity and affects a neuronal activity not mediated by toxicity. by NMDA. Preferably, the intestine disorder treated by the method is Crohn's disease or colitis. The present invention also relates to a method for the treatment of arthritis in an animal, which comprises administering to the animal an effective amount of a compound that inhibits PARP activity and affects a neuronal activity not mediated by NMDA toxicity. The present invention further relates to a method for the treatment of diabetes in an animal, which comprises administering to the animal an effective amount of a compound that inhibits PARP activity and affects a neuronal activity not mediated by NMDA toxicity. The present invention further relates to a method for the treatment of septic shock in an animal, which comprises administering to the animal an effective amount of a compound that inhibits PARP activity and affects a neuronal activity not mediated by NMDA toxicity. Preferably, the type of septic shock treated is endotoxic shock. The invention also relates to a method for the 6d treatment of cancer in an animal, which comprises administering to the animal an effective amount of a compound that inhibits PARP activity and affects a neuronal activity not mediated by NMDA toxicity. The invention also relates to the radiosensitization of tumor cells. The type of cancer or tumor cells can be selected from the group consisting of tumors that produce ACTH, acute lymphocytic leukemia, acute non-lymphocytic leukemia, adrenal cortex cancer, bladder cancer, brain cancer, breast cancer , cervical cancer, chronic lymphocytic leukemia, chronic myelocytic leukemia, colorectal cancer, cutaneous T-cell lymphoma, endometrial cancer, esophageal cancer, Ewing sarcoma, gallbladder cancer, hairy cell leukemia, head and neck cancer, Hodgkin's lymphoma , Kaposi's sarcoma, kidney cancer, liver cancer, lung cancer (small and / or small cells), malignant peritoneal effusion, malignant pleural effusion, melanoma, mesothelioma, multiple myeloma, neuroblastoma, non-Hodgkin's lymphoma, osteosarcoma, ovarian cancer, ovarian cancer (germ cells), pancreatic cancer, cancer of the penis, prostate cancer, retinoblastoma, cancer of the skin, soft tissue sarcoma, squamous cell carcinomas, stomach cancer, testicular cancer, thyroid cancer, trophoblastic neoplasms, uterine cancer, vaginal cancer, cancer of the vulva and Wilm's tumor.

The term "radiosensitizer", as used herein, is defined as a molecule, preferably a low molecular weight molecule, administered to animals in therapeutically effective amounts to increase the sensitivity of cells to be radiosensitized to electromagnetic radiation and / or to promote the treatment of diseases that can be treated with electromagnetic radiation. Diseases that can be treated with electromagnetic radiation include neoplastic diseases, benign and malignant tumors, and cancer cells. The treatment with electromagnetic radiation of other diseases not mentioned herein is also contemplated by the present invention. The terms "electromagnetic radiation" and "radiation", as used herein, include, but are not limited to, radiation having the wavelength of 10 to 10 meters. Preferred embodiments of the present invention employ electromagnetic radiation of: gamma radiation (from 10 to 10 meters), X-ray radiation (from 10 to 10 meters), ultraviolet light (from 10 nanometers to 400 nanometers), visible light (from 400 nanometers to 700 nanometers), infrared radiation (from 700 nanometers to 1.0 millimeters), and microwave radiation (from 1 millimeter to 30 centimeters). It is known that radiosensitizers increase the sensitivity of cancer cells to the toxic effects of electromagnetic radiation. Several mechanisms have been suggested for the mode of action of radiosensitizers in the literature, including: hypoxic cell radiosensitizers (eg, 2-nitroimidazole compounds, and benzotriazine dioxide compounds) promote reoxigenation of hypoxic tissue, and / or catalyze the generation of harmful oxygen radicals; the non-hypoxic cell radiosensitizers (eg, halogenated pyrimidines) can be DNA base analogues, and are preferably incorporated into the DNA of cancer cells, and thus promote the radiation-induced disruption of DNA molecules and / or prevent normal DNA repair mechanisms; and other different potential mechanisms of action that have been hypothesized for radiosensitizers in the treatment of diseases. Many cancer treatment protocols currently employ radiosensitizers activated by electromagnetic radiation from X-rays. Examples of X-ray-activated radiosensitizers include, but are not limited to, the following: metronidazole, misonidazole, desmethylmisonidazole, pimonidazole, etanidazole, nimorazole, mitomycin C, RSU 1069, SR 4233, E09, RB 6145, nicotinamide, -bro odeoxyuridine (BUdR), 5-iododeoxyuridine (IUdR), bromodeoxycytidine, fluorodeoxyuridine (FudR), hydroxyurea, cisplatin, and therapeutically effective analogs and derivatives thereof. Photodynamic therapy (PDT) of cancers uses visible light as the radiation activator of the sensitizing substance. Examples of the photodynamic radiosensitizers include the following, but are not limited to: hematoporphyrin derivatives, photofrina, benzoporphyrin derivatives, NPe6, tin etioporphyrin SnET2, pheoborbide-a, bacteriochlorophyll-a, naphthalocyanines, phthalocyanines, zinc phthalocyanine, and therapeutically effective analogs and derivatives thereof. The radiosensitizers may be administered in conjunction with a therapeutically effective amount of one or more other compounds, including, but not limited to: compounds that promote the incorporation of the radiosensitizers into the target cells; compounds that control the flow of therapeutics, nutrients, and / or oxygen to the target cells, chemotherapeutic substances that act on the tumor with or without additional radiation; or other therapeutically effective compounds for the treatment of cancer or other disease. Examples of additional therapeutic substances that can be used in conjunction with the radiosensitizers include, but are not limited to: 5-fluorouracil, leucovorin, 5'-amino-5-deoxythymidine, oxygen, carbogen, red blood cell transfusions, perfluorocarbons (eg, Fluosol-DA), 2,3-DPG, BW12C, blockers of the calcium channel, pentoxifylline, compounds against angiogenesis, hydralazine, and L-BSO. Examples of chemotherapeutic substances that can be used in conjunction with radiosensitizers include, but are not limited to: adriamycin, camptothecin, carboplatin, cisplatin, daunorubicin, docetaxel, doxorubicin, interferon (alpha, beta, gamma), interleukin 2, irinotecan , paclitaxel, topotecan, and therapeutically effective analogs and derivatives thereof. The present invention also relates to the treatment or prevention of tissue damage resulting from cell damage or death due to necrosis or apoptosis, and to conditions and diseases related thereto, including, but not limited to, renal failure, cachexia, retinal ischemia, skin aging, atherosclerosis, osteoarthritis, osteoporosis, chronic pain, acute pain, neuropathic pain, muscular dystrophy, skeletal muscle degenerative diseases involving replicative senescence, age-related macular degeneration, immune senescence, AIDS and other immune senescence diseases , and cancer; to prolong the life and proliferative capacity of cells; to alter the genetic expression of senescent cells; and to radiosensitize hypoxic tumor cells. The present invention still further relates to a method for inhibiting the activity of PARP in an animal, which comprises administering to the animal an effective amount of a compound that inhibits PARP activity, and that affects a neuronal activity not mediated by toxicity. by NMDA. The compounds used in each of the above methods of the invention, preferably interact with the PARP, forming at least one hydrogen bond with Ser and / or Gly in the PARP. Specifically, an NH group of the compound preferably forms a hydrogen bond with the Gly atom in the PARP. The length of this link is from about 1 to 5 Á, preferably 2 to 4 Á. Additionally, an O, S, or N atom of the compound preferably forms a hydrogen bond with the H atom of Ser. The length of this bond is from about 1 to 5 Á, preferably from about 2 to 4 Á. In a further preferred embodiment, the compound used in each of the above methods of the invention exhibits one to inhibit PARP in about 100 μM or lower, more preferably about 25 μM or lower. Compositions and Methods for Affecting Neuronal Activity Preferably, the compounds of the invention inhibit PARP activity, and are therefore believed to be useful for treating damage to neural tissue, particularly damage resulting from cerebral ischemia and injury from reperfusion or neurodegenerative diseases in animals. The term "nerve tissue" refers to the different components that make up the nervous system, including, without limitation, neurons, neural support cells, glia, Schwann cells, vasculature contained within, and supplied to, these structures, the system central nervous, the brain, the brainstem, the spinal cord, the junction of the central nervous system with the peripheral nervous system, the peripheral nervous system, and allied structures. In addition, according to the invention, an effective therapeutic amount of the compounds and compositions described above, are administered to the animals to affect a neuronal activity, particularly one that is not mediated by NMDA neurotoxicity. This neuronal activity may consist of the stimulation of damaged neurons, the promotion of neuronal regeneration, the prevention of neurodegeneration, and the treatment of a neurological disorder. In accordance with the above, the present invention further relates to a method for affecting a neuronal activity in an animal, which comprises administering an effective amount of the compound of the invention to the animal. Examples of neurological disorders that can be treated by the method of use of the present invention include, without limitation, trigeminal neuralgia; glossopharyngeal neuralgia; Bell's palsy; myasthenia gravis; muscular dystrophy; amyotrophic lateral sclerosis, progressive muscle atrophy 75; Progressive bulbar inherited muscular atrophy; syndromes of herniated, ruptured, or collapsed invertebrate discs; cervical spondylosis; plexus disorders; syndromes of destruction of the thoracic outlet; peripheral neuropathies, such as those caused by lead, dapsone, ticks, porphyria, or Guillain-Barré syndrome; Alzheimer disease; Huntington's disease; and Parkinson's disease. The term "neurodegenerative diseases" includes Alzheimer's disease, Parkinson's disease, and Huntington's disease. "Nervous function" refers to the different functions of the nervous system, which among other things, provide an awareness of the internal and external environments of the body, make possible the voluntary and reflex activities between the different structural elements of the organism, and balance the body's response to changes in the environment. The term "nervous insult" refers to any damage to nerve tissue and any incapacitation or death resulting therefrom. The cause of the nervous insult may be metabolic, toxic, neurotoxic, iatrogenic, thermal or chemical, and includes, without limitation, ischemia, hypoxia, stroke, trauma, surgery, pressure, mass effect, hemorrhage, radiation, vasospasm, neurodegenerative disease , infection, Parkinson's disease, amyotrophic lateral sclerosis (ALS), myelination / demyelination process, epilepsy, cognitive disorder, glutamate abnormality, and side effects of the same. The term "neuroprotective" refers to the effect of reducing, stopping, or ameliorating the nervous insult, and protecting, resuscitating, or reliving nervous tissue that has suffered a nervous insult. The term "prevent neurodegeneration" includes the ability to prevent neurodegeneration in patients diagnosed as having a neurodegenerative disease, or who are at risk of developing a neurodegenerative disease. The term also covers preventing further neurodegeneration in patients who are already suffering from, or who have symptoms of, a neurodegenerative disease. The term "treat" refers to: (i) preventing the occurrence of a disease, disorder or condition in an animal that may be predisposed to the disease, disorder and / or condition, but has not yet been diagnosed as having it; (ii) inhibit the disease, disorder or condition, that is, stop its development; and (iii) alleviating the disease, disorder or condition, i.e., causing the regression of the disease, disorder and / or condition. The method of the present invention is particularly useful for the treatment of a neurological disorder selected from the group consisting of: peripheral neuropathy caused by physical injury or disease state; trauma to the head, such as traumatic brain injury; physical damage to the spinal cord; embolism associated with brain damage, such as vascular embolism associated with hypoxia and brain damage, focal cerebral ischemia, global cerebral ischemia, and cerebral reperfusion injury; demyelination diseases, such as multiple sclerosis; and neurological disorders related to neurodegeneration, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis (ALS). The term "neural tissue damage resulting from ischaemia and reperfusion injury and neurodegenerative diseases" includes neurotoxicity, as seen in vascular embolism and in global and focal ischemia. Treatment of Other PARP-Related Disorders The compounds, compositions and methods of the invention can also be used to treat a cardiovascular disorder in an animal, by administering an effective amount of the compound of formula IV to the animal. For example, the compounds of the invention can treat or prevent damage to cardiovascular tissue resulting from cardiac ischemia or reperfusion injury. For example, reperfusion injury occurs at the end of cardiac bypass procedures, or during cardiac arrest, when the heart, once prevented from receiving blood, begins to reperfuse. As used herein, the term "cardiovascular disorders" refers to those disorders that can cause ischemia, or that are caused by reperfusion of the heart. Examples include, but are not limited to, coronary artery disease, angina pectoris, myocardial infarction, cardiovascular tissue damage caused by cardiac arrest, cardiovascular tissue damage caused by cardiac bypass, cardiogenic shock, and related conditions that are known to those of ordinary skill in the art, or involving dysfunction of, or damage to, the heart or vasculature, especially, but not limited to, tissue damage related to activation of PARP. The term "ischemia" refers to localized tissue anemia due to obstruction of the arterial blood influx. Global ischemia occurs when the blood flow to the entire brain ceases over a period of time. Global ischemia can result from cardiac arrest. Focal ischemia occurs when a portion of the brain is deprived of its normal blood supply. Focal ischemia can result from thromboembolic obstruction of a cerebral vessel, traumatic head injury, edema, or brain tumor. Even when it is transient, both global and focal ischemia 11 can cause widespread neuronal damage. Although nerve tissue damage occurs after hours or even days after the establishment of ischemia, permanent nerve damage may develop in the initial minutes after the blood flow to the brain ceases. Much of this damage has been attributed to the glutamate toxicity and the secondary consequences of tissue reperfusion, such as the release of vasoactive products by the damaged endothelium, and the release of cytotoxic products, such as free radicals and leukotrienes, by the damaged tissue. Ischemia may also occur in the heart in myocardial infarction and other cardiovascular disorders where the coronary arteries have been obstructed as a result of atherosclerosis, thrombus, or spasm. For example, it is believed that the methods of the invention are useful for treating cardiac tissue damage, particularly damage resulting from cardiac ischemia, or caused by reperfusion injury in mammals. The methods of the invention are particularly useful for the treatment of cardiovascular disorders selected from the group consisting of: coronary artery disease, such as atherosclerosis; angina pectoris, myocardial infarction, myocardial ischemia and cardiac arrest; cardiac derivation; and cardiogenic shock. The methods of the invention are especially useful in the treatment of acute forms of anterior cardiovascular disorders. In addition, the compounds of the invention can be used to treat arthritis; diabetes; septic shock, such as endotoxic shock; and inflammatory bowel disorders, such as colitis and Crohn's disease; to treat or prevent renal failure, cachexia, retinal ischemia, or chronic pain, acute pain, neuropathic pain; to alter gene expression in senescent cells by increasing the expression of genes specific for young cells, and / or decreasing the expression of specific genes of senescent cells; and to prolong and increase the life or proliferative capacity of the cells; and to treat a disease or disease conditions induced or exacerbated by cellular senescence, such as skin aging, Alzheimer's disease, atherosclerosis, osteoarthritis, osteoporosis, age-related macular degeneration, muscular dystrophy or other degenerative skeletal muscle diseases that involve replicative senescence, and immune senescence, including diseases such as AIDS, which result in senescence - immune. In addition, the methods of the invention can be used to treat cancer, and to radiosensitize tumor cells. The term "cancer" is widely interpreted. The compounds of the present invention can be "anticancer substances", the term also encompassing "anti-tumor cell growth substances" and "anti-neoplastic agents". For example, the methods of the invention are useful for the treatment of cancers, and for radiosensitizing tumor cells of cancers, such as tumors that produce ACTH, acute lymphocytic leukemia, acute non-lymphocytic leukemia, adrenal cortex cancer, bladder cancer, brain cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia, chronic myelocytic leukemia, colorectal cancer, cutaneous T-cell lymphoma, endometrial cancer, esophageal cancer, Ewing's sarcoma, gallbladder cancer, leukemia hair cells, head and neck cancer, Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer, liver cancer, lung cancer (small and / or small cells), malignant peritoneal effusion, malignant pleural effusion, melanoma, mesothelioma, multiple myeloma, neuroblastoma, non-Hodgkin's lymphoma, osteosarcoma, ovarian cancer, ovarian cancer (germ cells), cancer prostate, pancreatic cancer, cancer of the penis, retinoblastoma, skin cancer, soft tissue sarcoma, squamous cell carcinomas, stomach cancer, testicular cancer, thyroid cancer, trophoblastic neoplasms, uterine cancer, vaginal cancer, cancer of the vulva and Wilm's tumor. Administration For medical use, the required amount of a compound of Formula IV to achieve a therapeutic effect will vary according to the particular compound administered, the route of administration, the mammal under treatment, and the particular disorder or disease concerned. An adequate systemic dose of a compound of Formula IV for a mammal suffering from, or likely to suffer from, any condition described herein, is typically on the scale of about 0.1 to about 100 milligrams of base per kilogram of body weight, preferably from about 1 to about 10 milligrams / kilogram of body weight of the mammal. It is understood that the ordinarily skilled physician or veterinarian will be able to easily determine and prescribe the amount of the compound effective for the desired prophylactic or therapeutic treatment. By doing this, the doctor or veterinarian can use an intravenous bolus, followed by an intravenous infusion and repeated administrations, as deemed appropriate. In the methods of the present invention, the compounds can be administered, for example, orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, sublingually, vaginally, intraventricularly, or by means of an implanted reservoir, in formulations of dosage containing pharmaceutically acceptable carriers, auxiliaries and vehicles, non-toxic, conventional. Parenteral includes, but is not limited to, the following administration examples: intravenous, subcutaneous, intramuscular, intraspinal, intraosseous, intraperitoneal, intrathecal, intraventricular, intrasternal, or intracranial injection, and infusion techniques, such as by subdural pump. Invasive techniques are preferred, particularly direct administration to damaged neuronal tissue. Although it is possible for the compounds of Formula IV to be administered alone, it is preferable to provide them as a part of a pharmaceutical formulation. To be effective therapeutically as central nervous system targets, the compounds used in the method of the present invention should easily penetrate the blood-brain barrier when administered peripherally. However, compounds that can not penetrate the blood-brain barrier can still be effectively administered through an intraventricular route.

The compounds used in the methods of the present invention can be administered by a single dose, multiple separate doses, or continuous infusion. Because the compounds are small, easily diffusible, and relatively stable, they are well suited for continuous infusion. A pump element, particularly a subcutaneous or subdural pump element, is preferred for continuous infusion. For the methods of the present invention, any effective administration regimen regulating the time and sequence of the doses can be used. Doses of the compounds preferably include pharmaceutical dosage units comprising an effective amount of the active compound. An "effective amount" means an amount sufficient to inhibit the activity of PARP, and / or derive the desired beneficial effects thereof through the administration of one or more of the pharmaceutical dosage units. In a particularly preferred embodiment, the dose is sufficient to prevent or reduce the effects of vascular embolism or other neurodegenerative diseases. An exemplary daily dosage unit for a vertebrate host comprises an amount from about 0.001 milligrams / kilogram to about 50 milligrams / kilogram. Typically, dosage levels of the order of about 0.1 milligrams to about 10,000 milligrams of the active ingredient compound are useful in the treatment of the above conditions, with preferred levels being about 0.1 milligrams to about 1,000 milligrams. The specific dose level for any particular patient will vary depending on a variety of factors, including the activity of the specific compound employed; age, body weight, general health, sex, and the patient's diet; the time of administration; the rate of excretion; any combination of the compound with other drugs; the severity of the particular disease being treated; and the form and route of administration. Normally, dosing-effect results provide a useful guide on the appropriate doses for administration to the patient. Studies in animal models may also be useful. Considerations for determining appropriate dose levels are well known in the art. In the methods for the treatment of nerve aggression (particularly acute ischemic embolism and global ischemia caused by drowning or head trauma), the compounds of the invention can be co-administered with one or more different therapeutic substances, preferably substances that can reduce the risk of embolism (such as aspirin), and more preferably, substances that can reduce the risk of a second ischemic event (such as ticlopidine). The compounds and compositions can be co-administered with one or more therapeutic substances, either (i) together in a single formulation, or (ii) separately in individual formulations designed for optimal release rates of their respective active substance. When the compounds used in the methods of the invention are administered in combination with one or more other therapeutic substances, the specific dose levels for these substances will depend on considerations such as those identified above for the compositions and methods of the invention in general.

For example, the following Table II provides the • known mean dosages for selected chemotherapeutic agents that can be administered in combination with the compounds of the invention for these diseases or different cancers.

TABLE II For the methods of the present invention, any administration regimen that regulates the time and sequence of delivery of the compound may be used, and may be repeated as necessary to effect the treatment. This regimen may include pretreatment and / or co-administration with additional therapeutic substances. To maximize the protection of nerve tissue from nerve aggression, the compounds of the invention should be administered to the affected cells as soon as possible. In situations where nervous aggression is anticipated, the compounds are conveniently administered prior to the expected nerve aggression. These situations of increased possibility of nerve aggression include surgery, such as carotid endarterectomy, cardiac, vascular, aortic, orthopedic surgery; endovascular procedures, such as arterial catheterization (carotid, vertebral, aortic, cardia, renal, spinal, Adamkiewicz); injections of embolic substances; the use of coils or balloons for hemostasis; interruptions of vascularity for treatment of brain injuries; and predisposing medical conditions, such as transient ischemic attacks crescendo, emboli, and sequential emboli. When the previous treatment for embolism or ischemia is impossible or impractical, it is important to bring the compounds of the invention in contact with the affected cells as soon as possible, either during or after the event. However, in the time period between embolisms, diagnostic and treatment procedures should be minimized to save the cells from additional damage and death. Accordingly, a particularly convenient mode of administration with a patient diagnosed with multiple acute vascular emboli is by implantation of a subdural pump to deliver the compounds of the invention directly to the area of infarction of the brain. Even when comatose, the patient is expected to recover more quickly than he or she would without this treatment. Moreover, in any patient's conscious state, any residual neurological symptoms, as well as the reoccurrence of the embolism, are expected to be reduced. With respect to patients diagnosed with other acute disorders that are believed to be related to PARP activity, such as diabetes, arthritis, and Crohn's disease, the compound of the invention should also be administered as soon as possible in a single dose or in divided doses. Depending on the symptoms presented by the patient, and the degree of response of the initial administration of the compound of the invention, the patient can additionally receive additional doses of the same or different compounds of the invention, by one of the following routes: parenterally, such as by injection or by intravenous administration; orally, such as by capsule or tablet; by implantation of a biodegradable and biocompatible polymer matrix delivery system comprising the compound; or by direct administration to the infarct area, by inserting a subdural pump or a central line. The treatment is expected to alleviate the disorder, either in part or in its entirety, and to develop fewer additional presentations of the disorder. The patient is also expected to suffer less residual symptoms. When the patient is diagnosed with an acute disorder prior to the availability of the compounds of the invention, the patient's condition may deteriorate due to the acute disorder, and may become a chronic disorder by the time the compounds are available. Even when a patient receives a compound of formula IV for the chronic, it is also expected that the patient's condition will stabilize and actually improve as a result of receiving the compound. EXAMPLES The following examples are illustrative of the preferred embodiments of the invention, and should not be construed to limit the present invention thereto. All molecular weights of the polymer are average molecular weights. All percentages are based on the weight percentage of the final delivery system or the prepared formulation, unless otherwise indicated, and all totals are equal to 100 percent by weight. Example 1; Approximate C ^ Q Data for Selected Compounds The IC ^ Q with respect to PARP inhibition, for different compounds, was determined by a PARP assay using purified recombinant human PARP from Trevigen (Gaithersburg, MD), as follows: The PARP enzyme assay was established on ice in a volume of 100 microliters consisting of 10 mM Tris-HCl (pH of 8.0), 1 mM MgCl 2, 28 mM KCl, 28 mM NaCl, 0.1 milligram / milliliter of herring sperm DNA (activated as a supply of 1 milligram / milliliter for 10 minutes in a 0.15 percent hydrogen peroxide solution), [3H] nicotinamide-adenine dinucleotide 3.0 micromolar (470 mci / millimole), 7 micrograms / milliliter of PARP enzyme, and different concentrations of the compounds to be tested. The reaction was initiated by incubating the mixture at 25 ° C. After 15 minutes of incubation, the reaction was terminated by the addition of 500 microliters of ice cold 20 percent (w / v) trichloroacetic acid. The formed precipitate was transferred to a glass fiber filter (Packard Unifilter-GF / B), and washed three times with ethanol. After the filter was dried, radioactivity was determined by scintillation counting.

Using the PARP assay described above, approximate IC 50 values were obtained for the following compounds: 1Ó4 Example 2: Neuroprotective effect of DPO on Focal Cerebral Ischem in Rats Focal cerebral ischemia was produced by cauterization of the right distal MCA (middle cerebral artery), with bilateral temporary occlusion of the common carotid artery, in male Long-Evans rats during 90 minutes. All procedures performed on the animals were approved by the University Institutional Committee on Animal Care and Use of the University of Pennsylvania. A total of 42 rats (weights: 230 to 340 grams) obtained from Charles River were used in this study. The animals were fasted overnight with free access to water before the surgical procedure. Two hours before occlusion of the middle cerebral artery, different amounts were dissolved (control, n = 14, 5 milligrams / kilogram, n = 7, 10 milligrams / kilogram, n = 7, 20 milligrams / kilogram, n = 7; and 40 milligrams / kilogram, n = 7) of the compound, 3,4-dihydro-5- [4-1-piperidinyl) -butoxy] -1 (2H) -isoquinolinone ("DPQ") in dimethyl sulfoxide (DMSO) using a sonicator. A volume of 1.28 milliliters / kilogram of the resulting solution was injected intraperitoneally into 14 rats. The rats were then anesthetized with halothane (4 percent for induction, and 0.8 percent to 1.2 percent for the surgical procedure) in a mixture of 70 percent nitrous oxide and 30 percent oxygen. The body temperature was monitored by a rectal probe, and maintained at 37.5 + 0.5 ° C with a heating blanket regulated by a homeothermic blanket control unit (Harvard Apparatus Limited, Kent, UK). A catheter (PE-50) was placed in the tail artery, blood pressure was continuously monitored and recorded on a Grass polygraph recorder (Model 7D, Grass Instruments, Quincy, Massachusetts). Samples were also taken for the blood gas analysis (arterial pH, Pa02 and PaCOz) of the tail artery catheter, and were measured with a blood gas analyzer (ABL 30, Radiometer, Copenhagen, Denmark). Arterial blood samples were obtained 30 minutes after occlusion of the middle cerebral artery. The head of the animal was placed in a stereotaxic frame, and a right parietal incision was made between the right lateral canthus and the external auditory meatus. Using a dental drill constantly cooled with serum, a hole of 3 mm hole was prepared on the cortex provided by the middle cerebral artery, 4 mm lateral to the sagittal suture, and 5 mm caudal to the coronal suture. The dura mater and a thin layer of internal bone were stored, taking care to place the probe over an area of the tissue that did not have large blood vessels. The flow probe (diameter of the tip of 1 millimeter, separation of the fiber of 0.25 millimeters) was lowered to the bottom of the hole of the cranial cavity using a micromanipulator. The probe was kept stationary by a probe holder secured to the skull with dental cement. The flow of microvascular blood in the right parietal cortex was continuously monitored with a laser Doppler flow meter (FloLab, Moor, Devon, United Kingdom, and Periflux 4001, Perimed, Stockholm, Sweden). Focal cerebral ischemia was produced by cauterization of the distal portion of the right middle cerebral artery with bilateral temporal occlusion of the common carotid artery (CCA), using the procedure of Chen et al., "A Model of Focal Ischemic Stroke in the Rat: Reproducible Extensive Cortical Infarction, "Stroke 17: 738-43 (1986), and / or Liu et al.," Polyethylene Glycol-Conjugated Superoxide Dismutase and Catalase Reduce Ischemic Brain Injury, "Am. J. Physiol. 256-H589-93 (1989), both of which are incorporated herein by reference. Specifically, the bilateral common carotid arteries were isolated, and loops made from the polyethylene catheter (PE-10) were carefully passed around the common carotid arteries for a posterior remote occlusion. The incision made previously to place the laser Doppler probe was extended to allow observation of the rostral end of the zygomatic arch at the fusion point, using a dental drill, and the hard mater that was overlapping the common carotid artery was cut. . The middle cerebral artery distal to its junction with the inferior cerebral vein was lifted with a fine stainless steel hook attached to a micromanipulator, and next to the bilateral occlusion of the common carotid artery, the middle cerebral artery was cauterized with an electro-coagulator . The hole in the hole was covered with a small piece of Gelform, and the wound was sutured to keep the brain temperature within the normal or near normal range. After 90 minutes of occlusion, the loops of the carotid were released, the arterial catheter was removed from the tail, and all the wounds were sutured. Gentamicin sulfate (10 milligrams / milliliter) was applied topically to the wounds to prevent infection. The anesthetic was discontinued, and the animal was returned to its cage after waking up. They gave water and food to taste. Two hours after occlusion of the middle cerebral artery, the animals were given the same doses of the PARP inhibitor as in the previous treatment. Twenty-four hours after occlusion of the middle cerebral artery, the rats were sacrificed with an intraperitoneal injection of sodium pentobarbital (150 milligrams / kilogram). The brain was carefully removed from the skull, and chilled in artificial ice-cold CSF for 5 minutes. The cooled brain was then sectioned in the coronal plane at 2 millimeter intervals, using a rodent brain matrix (RBM-4000C, ASI Instruments, Warren, Michigan). The brain slices were incubated in phosphate-buffered serum containing 2, 3, 5, 5-triphenyltetrazolium chloride (TTC) at 37 ° C for 10 minutes. Color photographs were taken of the back surface of the stained slices, and were used to determine the damaged area at each cross-sectional level, using a computer-based image analyzer (NIH Image 1.59). To avoid artifacts due to edema, the damaged area was calculated by subtracting the normal tissue area in the hemisphere ipsilateral to the embolism, from the area of the hemisphere contralateral to the embolism, by the method of Swanson et al, "A Semiautomated Method for Measuring Brain Infarct Volume ", J". Cereb. Blood Flow Metabol. 10: 290-93 (1990), the disclosure of which is incorporated herein by reference. The total volume of the infarction was calculated by adding up the damaged volume of the brain slices. The cauterization of the distal portion of the right middle cerebral artery with the bilateral temporal occlusion of the common carotid artery consistently produced a well-recognized cortical infarction in the territory of the right middle cerebral artery of each test animal. There was an apparent uniformity in the distribution of the damaged area, measured by TTC staining in each group, as shown in Figure 1. In Figure 1, the distribution of the infarct area was measured in cross-section at representative levels throughout of the rostrocaudal axis, from the interaural line in the untreated animals, and in the animals treated with 10 milligrams / kilogram of 3, 4-dihydro-5- [4- (1-piperidinyl) -butoxy] -1 (2H) - isoquinolinone. The damage area was expressed as average +, standard deviation. Significant differences were indicated between the treated group with 10 milligrams and the control group (p <0.02, p <0.01, p <0.001). The curves of 5 milligrams / kilogram and 20 milligrams / kilogram dropped approximately in half between the control and the 10 milligram / kilogram curves, while the 40 milligram / kilogram curve was close to the control. The curves of 5, 20 and 40 milligrams / kilogram were omitted for clarity.

The inhibition of PARP led to a significant decrease in the volume damaged in the treated group with 5 milligrams / kilogram (106.7 ± 23.2 mm, p <0.001), the group treated with 10 milligrams / kilogram (76.4 +.16.8 mm3, p < 0.001), and the group treated with 20 milligrams / kilogram (110.2 + 42.0 mm, p < 0.01), compared to the control group (165.2 + 34.0 mm). The data are expressed as mean ± standard deviation. The meaning of the differences between the groups was determined, using a variation analysis (ANOVA) followed by the Student's t-test for individual comparisons.

There was no significant difference between the control and the group treated with 40 milligrams / kilogram. However, there were significant differences between the treated group with 5 milligrams / kilogram and the treated group with 10 milligrams / kilogram (p <0.02), and between the treated group with 10 milligrams / kilogram and the treated group with 40 milligrams / kilogram (p <0.01), as shown in Figure 2. In Figure 2, the effect of peritoneal administration of 3,4-dihydro-5- [4- (1-piperidinyl) -butoxy] - was illustrated graphically. 1 (2H) -isoquinolinone on the infarct volume. Infarct volumes were expressed as mean + standard deviation. Significant differences were indicated between the treated groups and the control group (p <0.01, p < 0.001). The reason why a high dose (40 milligrams / kilogram) of the PARP inhibitor, 3,4-dihydro-5- [4- (1-piperidinyl) -butoxy] -1 (2H) -isoquinolinone, was unclear less neuroprotective. The dose response curve in U-shape may suggest dual effects of the compound. However, above all, the in vivo administration of the inhibitor led to a substantial reduction in infarct volume in the model of focal cerebral ischemia in the rat. This result indicated that the activation of PARP plays an important role in the pathogenesis of brain damage in cerebral ischemia. The values of the arterial blood gases (Pa02, PaC02 and pH) were within the physiological range in the control and in the treated groups, without significant differences in these parameters among the five groups, as shown later in Table 2. A mean arterial blood pressure (PSAM) of "continuous state" was taken immediately after the completion of the surgical preparation, just before the occlusion; a mean arterial blood pressure of "ischemia" was taken as the average mean arterial blood pressure during occlusion. See Table III below: TABLE III = Significantly different from the continuous state value, p < 0.05. = Significantly different from the continuous state value, p < 0.01.

There were no significant differences in any physiological parameter, including mean arterial blood pressure (PSAM), before occlusion of the middle cerebral artery, ll2, and common carotid artery among the five groups. Although mean arterial blood pressure increased significantly following occlusion in all five groups, there was no significant difference in mean arterial blood pressure during the period of occlusion between the groups. Because the blood flow values obtained from the laser Doppler were in arbitrary units, only percentage changes of the baseline were reported (before occlusion). Right occlusion of the middle cerebral artery, and bilateral occlusion of the common carotid artery, produced a significant decrease in relative blood flow in the right parietal cortex up to 20.8 + 7.7 percent of the baseline in the control group (n = 5), 18.7 + 7.4 percent in the group treated with 5 milligrams / kilogram (n = 7), 21.4 + 7.7 percent in the group treated with 10 milligrams / kilogram (n = 7), and 19.3 + 11.2 percent in the group treated with 40 milligrams / kilogram (n = 7). There would be no significant differences in the blood flow response to occlusion between the four groups. In addition, blood flow did not show significant changes throughout the occlusion period in any group. Following the release of the carotid occlusions, a good recovery of blood flow (sometimes hyperemia) was observed in the right territory of the middle cerebral artery of all the animals. The reperfusion of the ischemic tissue resulted in the formation of NO and peroxynitrite, in addition to free radicals derived from oxygen. It has been shown that all these radicals cause breaks in the DNA chain, and that they activate PARP. This example provided evidence that the related compounds of the present invention are effective in inhibiting PARP activity. Step 3: Essay to Determine the Effects Neuroprotectors About Focal Brain Ischemia in Rats Focal cerebral ischemia experiments are performed using male Wistar rats weighing 250 grams to 300 grams, which are anesthetized with 4 percent halothane. Anesthesia is maintained with halothane from 1.0 to 1.5 percent until the end of surgery. The animals are installed in a warm environment to avoid a decrease in body temperature during surgery. A cervical incision is made from the anterior midline. The right common carotid artery (CCA) is exposed and is isolated from the vagus nerve. A silk suture is placed, and tied around the common carotid artery near the heart. The external carotid artery (ACE) is then exposed and ligated with a silk suture. A perforation is made in the common carotid artery, and a small catheter is gently advanced (PE 10, Ulrich &Co., St-Gallen, Switzerland) to the lumen of the internal carotid artery (ICA). The pterygopalatine artery is not obstructed. The catheter is tied in place with a silk suture. A 4-0 nylon suture (Braun Medical, Crissier, Switzerland) is then inserted into the lumen of the catheter, and pushed until the tip blocks the anterior cerebral artery. The length of the catheter in the internal carotid artery is approximately 19 millimeters from the origin of the external carotid artery. The suture is held in this position by heat catheter obstruction. One centimeter of catheter and nylon suture are left protruding, so that the suture can be removed to allow reperfusion. The incision of the skin is then closed with wound clips. The animals are kept in a warm environment during the recovery from anesthesia. Two hours later, the animals are re-anesthetized, the fasteners are discarded, and the wound is reopened. The catheter is cut, and the suture is pulled out. The catheter is then again cured by heat, and wound fasteners are placed over the wound. The animals are left to survive for 24 hours with free access to food and water. The rats are then sacrificed with C02, and decapitated. The brains are removed immediately, frozen on dry ice, and stored at -80 ° C. The brains are then cut into sections of 0.02 millimeters thick in a cryocut at -19 ° C, selecting one out of every 20 sections for further examination. The selected sections are stained with cresyl violet according to the Nissl procedure. Each stained section is examined under a light microscope, and the regional area of infarction is determined according to the presence of cells with morphological changes. Different doses of the compounds of the invention are tested in this model. The compounds are administered in a single dose or in a series of multiple doses, intraperitoneally or intravenously, at different times, both before and after the establishment of ischemia. It is found that the compounds of the invention provide ischemia protection in the range of about 20 to 80 percent. Example 4; Effects on Heart Ischemia / Rat Reperfusion Injury Female Sprague-Dawley rats, each weighing approximately 300 to 350 grams, are anesthetized with intraperitoneal ketamine, in a dose of 150 milligrams / kilogram. The rats are intubated endotracheally, and ventilated with ambient air enriched with oxygen, using a Harvard rodent ventilator. Polyethylene catheters inserted into the carotid artery and into the femoral vein are used to monitor arterial blood pressure and fluid administration, respectively. The arterial pC02 is maintained between 35 and 45 mm Hg, by adjusting the speed of the respirator.

The breasts of rats are opened by median sternotomy, the pericardium is cut, and the hearts are cradled with a latex membrane. The hemodynamic data are obtained in the baseline after at least one stabilization period of 15 minutes after the end of the surgical operation. The coronary artery LAD (left anterior descending) is ligated for 40 minutes, and then re-infused for 120 minutes. After a 120-minute reperfusion, the left anterior descending artery is obstructed again, and a 0.1 milliliter bolus of monastral blue dye is injected into the left atrium to determine the region at ischemic risk. Then the hearts are stopped with potassium chloride, and cut into five transverse slices of 2 to 3 millimeters thick. Each slice is weighed and incubated in a 1 percent solution of trimethyltetrazolium chloride, to visualize the infarcted myocardium located within the region at risk. The infarct size is calculated by summing the values for each left ventricular slice, and is additionally expressed as a fraction of the region at risk of the left ventricle. Different doses of the compounds of the invention are tested in this model. The compounds are given either in a single dose or in a series of multiple doses, intraperitoneally or intravenously, at different times, both before and after the establishment of ischemia. It is found that the compounds of the invention have ischemia / reperfusion injury protection in the range of 10 to 40 percent. Accordingly, they protect against ischemia-induced degeneration of rat hippocampal neurons in vitro. Example 5: Protection of Retinal Ischemia A newly diagnosed patient with acute retinal ischemia is immediately administered in a parenteral manner, either by intermittent or continuous intravenous administration, a compound of Formula I, either as a single dose, or as a series of divided doses of the compound. After this initial treatment, and depending on the neurological symptoms present by the patient, the patient may optionally receive the same compound or a different compound of the invention in the form of another parenteral dose. The inventors expect that a significant prevention of neural tissue damage will be followed, and that the neurological symptoms of the patient will be considerably reduced due to the administration of the compound, leaving less residual neurological effects after the embolism. In addition, re-incidence of retinal ischemia is expected to be prevented or reduced. Example 6: Treatment of Retinal Ischemia One patient has been diagnosed with acute retinal ischemia. Immediately, a physician or a nurse parenterally administers a compound of Formula I, either as a single dose, or as a series of divided doses. The patient also receives the same or a different PARP inhibitor, by intermittent or continuous administration, by implantation of a biodegradable and biocompatible polymer matrix delivery system, comprising a compound of Formula I, or by means of a pump Subdural inserted to deliver the compound directly to the infarct area of the brain. The inventors expect the patient to awaken from coma more quickly than if the compound of the invention were not administered. The treatment is also expected to reduce the severity of the patient's residual neurological symptoms. In addition, the re-incidence of retinal ischemia is expected to be reduced. Example 7: Protection of Vascular Embolism A patient newly diagnosed with acute vascular embolism is immediately administered in a parenteral manner, either by intermittent or continuous intravenous administration, a compound of Formula IV, either as a single dose or as a series of divided doses of the compound. After this initial treatment, and depending on the neurological symptoms present by the patient, the patient may optionally receive the same or a different compound of the invention in the form of another parenteral dose. The inventors expect that a significant prevention of neural tissue damage will be followed, and that the neurological symptoms of the patient will be significantly reduced due to the administration of the compound, leaving less residual neurological effects after the embolism. In addition, it is expected that the re-incidence of vascular embolism will be prevented or reduced. Example 8; Vascular Embolism Treatment One patient has been diagnosed with multiple acute vascular emboli, and is comatose. Immediately, a physician or nurse parenterally administers a compound of Formula IV, either as a single dose, or as a series of divided doses. Due to the comatose state of the patient, the patient also receives the same or a different PARP inhibitor, by intermittent or continuous administration, by implantation of a biodegradable and biocompatible polymeric matrix delivery system comprising a compound of Formula IV , or by means of a subdural pump inserted to deliver the compound directly to the area of • Brain infarction. The inventors expect the patient to awaken from coma more quickly than if the compound of the invention were not administered. The treatment is also expected to reduce the severity of the patient's residual neurological symptoms. In addition, the re-incidence of vascular embolism is expected to be reduced. Example 9: Prevention of Cardiac Reperfusion Injury A patient is diagnosed with life-threatening cardiomyopathy, and requires a heart transplant. Until a donor heart is found, the patient is maintained with Extra Corpuscle Oxygenation Monitoring (MOCE). Then a donor heart is located, and the patient undergoes a surgical transplant procedure, during which the patient is placed with a heart-lung pump. The patient receives a compound of the intracardiac invention within a specified period of time, before redirecting his circulation from the heart-lung pump to his new heart, thus preventing cardiac reperfusion injury when the heart begins to beat. new heart regardless of the external heart-lung pump. Example 10: Septic Shock Test Groups of 10 male C57 / BL mice, weighing 18 to 20 grams, were given a test compound, 1-carboxynaphthalene-1-carboxamide, in doses of 60, 20, 6 and 2 milligrams / kilogram, daily, by intraperitoneal injection (IP) for three consecutive days. Each animal was stimulated first with lipopolysaccharide (LPS, from E. coli, LD100, 20 milligrams / animal, intravenously) plus galactosamine (20 milligrams / animal, intravenously). The first dose of the test compound in a suitable vehicle was given 30 minutes after the stimulus, and the second and third doses were given 24 hours later, on day 2 and day 3, respectively, receiving only the surviving animals. second or third dose of the test compound. Mortality was recorded every twelve hours after the stimulus during the three-day trial period. 1-carboxynaphthalene-1-carboxamide provided protection against mortality from septic shock of approximately 40 percent. Based on these results, it is expected that other compounds of the invention provide protection against mortality exceeding about 35 percent. Example 11: Radiosensitization in vi tro The human prostate cancer cell line, PC-3s, was coated in 6-well dishes, and grown in single layer cultures in RPMI1640 supplemented with 10 percent fetal calf serum. . Cells are maintained at 37 ° C in 5 percent C02 and 95 percent air. The cells were exposed to a dose response (0.1 mM to 0.1 μM) of 3 different PARP inhibitors of Formula I disclosed herein, before irradiation at a sublethal dose level. For all treatment groups, the six-well plates were exposed to room temperature in a Seifert irradiator of 250 kV / l5mA with 0.5 mm Cu / 1 mm. Cell viability was examined by the exclusion of 0.4 percent typhine blue. The exclusion of the dye was evaluated visually by the microscope, and the number of viable cells was calculated by subtracting the number of cells from the number of viable cells, and dividing by the total number of cells.

Cell proliferation indices were calculated by the amount of H-thymidine incorporation after irradiation. The PARP inhibitors show radiosensitization of the cells. Example 12: Live Radiosensitization Before undergoing radiation therapy to treat cancer, a patient is administered an effective amount of a compound or a pharmaceutical composition of the present invention. The compound or pharmaceutical composition acts as a radiosensitizer, and makes the tumor more susceptible to radiation therapy. Example 13: Measurement of Altered Gene Expression in Senescent MRNA Cells Human fibroblast BJ cells, in Duplication of Population (DLP) 94, are coated in a medium of regular growth, and then they are changed to a low serum medium to reflect the physiological conditions described in Linskens, et al., Nucleic Acids Res. 23: 16: 3244 -3251 (1995). A DMEM / 199 medium supplemented with 0.5 percent calf bovine serum is used. The cells are treated daily for 13 days with the PARP inhibitor of Formula I as disclosed herein. The control cells are treated with and without the solvent used to administer the PARP inhibitor. Old and untreated young control cells are treated for comparison. RNA is prepared from the treated and control cells, according to the techniques described in the publication of TCP Number 96/13610, and Northern staining is conducted. The specific probes for genes related to senescence are analyzed, and the treated and control cells are compared. In the analysis of the results, the lowest level of genetic expression is arbitrarily set at one, to provide a basis for comparison. Three genes particularly relevant to age-related changes in the skin are collagen, collagenase and elastin. West, Arch. Derm. 130: 87-95 (1994). The elastin expression of the cells treated with the PARP inhibitor of Formula I is increased significantly compared to the control cells. Elastin expression is significantly higher in young cells, compared to senescent cells, and therefore, treatment with the PARP inhibitor of Formula I causes the levels of elastin expression in senescent cells to change, up to levels similar to those found in much younger cells. In a similar manner, a beneficial effect on the expression of collagenase and collagen is seen with the treatment with the PARP inhibitors of Formula I. Example 14: Measurement of the Protein of Altered Genetic Expression in Senescent Cells Approximately 105 BJ cells, in Duplication of Population of 95-100, they are covered and they are grown in plates of 15 centimeters. The culture medium is DMEM / 199 supplemented with 10 percent calf bovine serum. The cells are treated daily for 24 hours with the PARP inhibitors of Formula I (100 micrograms / 1 milliliter of the medium). Cells are washed with phosphate buffered solution (SRF), then permeabilized with 4 percent paraformaldehyde for 5 minutes, then washed with phosphate buffered serum, and treated with 100 percent cold methanol for 10 minutes. The methanol is removed, and the cells are washed with phosphate-buffered serum, and then treated with 10 percent serum to block non-specific antibody binding. Approximately 1 milliliter of the appropriate commercially available antibody solutions (1: 500 dilution, Vector) is added to the cells and the mixture is incubated for 1 hour. The cells are rinsed and washed three times with phosphate-buffered serum. A secondary antibody, goat anti-mouse IgG (1 milliliter) with a biotin label, is added, along with 1 milliliter of a solution containing streptavidin conjugated with alkaline phosphatase, and 1 milliliter of NBT reagent (Vector). The cells are washed, and changes in gene expression are observed colorimetrically. Four genes specific for senescence - collagen I, collagen III, collagenase, and gamma-interferon - are monitored in senescent cells treated with the PARP inhibitor of Formula I, and the results show a decrease in gamma-interferon expression , without an observable change in the expression levels of the other three genes, demonstrating that the PARP inhibitors of Formula I can alter the specific gene expression of senescence. Example 15: Proliferation or Increase in Proliferative Capacity and Life of Cells To demonstrate the effectiveness of the present method to prolong the proliferative capacity and the life of the cells, human fibroblast cell lines (either W138 in Population Duplication (DLP) of 23, or BJ cells in a Population Replication of 71) are thawed and coated on T75 flasks, and allowed to grow in a normal medium ( DMEM / M199 plus 10 percent calf bovine serum) for about a week, at which time the cells are confluent, and therefore, the cultures are ready to subdivide. At the time of subdivision, the medium is aspirated, and the cells are rinsed with phosphate-buffered serum (SRF) and then trypsinized. Cells are counted with a Coulter counter and coated at a density of 10 5 cells per cm 2 in 6-well tissue culture dish, in DMEM / 199 medium supplemented with 10 percent calf bovine serum and varying amounts (0.10 μM, and 1 mM: from a 100X delivery solution in a DMEM / M199 medium) of a PARP inhibitor of Formula I as disclosed herein. This process is repeated every 7 days, until it seems that the cells stop dividing. The untreated cells (control) reach senescence, and stop dividing after approximately 40 days in culture. The treatment of the cells with 10 μM 3-AB seems to have little or no effect, in contrast to the treatment with 100 μM 3-AB, which seems to prolong the life of the cells, and the treatment with 1 M 3-AB which increases dramatically the life and the proliferative capacity of the cells. Cells treated with 1 mM 3-AB are still divided after 60 days in culture. Example 16: Neuroprotective Effects of Formula I on Chronic Constriction Injury (CCL) in Rats Adult male Sprague-Dawley rats, 300 to 350 grams, are anesthetized with 50 milligrams / kilogram of intraperitoneal sodium pentobarbital. The nerve ligament is performed by exposing one side of the sciatic nerves of the rat, and dissecting a nerve segment of 5 to 7 millimeters long, and closing with four loose ligatures to 1.0-1.5 millimeters, followed by implantation of an intrathecal catheter , and the insertion of a polyethylene tube flooded with gentamicin sulfate (PE-10) in the subarachnoid space through an incision in the cistern magna. The caudal end of the catheter is gently threaded into the lumbar enlargement, and the rostral end is secured with dental cement to a screw embedded in the skull, and the skin wound is closed with wound fasteners. Thermal hyperalgesia is evaluated in radiant heat using a leg withdrawal test. The rat is placed in a plastic cylinder on a 3-millimeter thick glass plate, with a radiant heat source from a projection bulb placed directly below the plantar surface of the rat's hindpaw. Paw withdrawal latency is defined as the time elapsed since the establishment of the stimulus by radiant heat until the removal of the hind paw of the rat. Mechanical hyperalgesia is evaluated by placing the rat in a cage with a bottom made of perforated metal foil with many small square holes. The duration of removal of the paw is recorded after mincing the average plantar surface of the hind paw of the rat with the tip of a safety spike inserted through the bottom of the cage. Mechano allodynia is evaluated by placing a rat in a cage similar to the previous test, and applying von Frey filaments in ascending order of bending strength, from 0.07 to 76 grams, to the average plantar surface of the rat's hindpaw. A von Frey filament is applied perpendicular to the skin, and pressed slowly until it folds. A threshold response force is defined as the first filament in the series that causes at least one removal of the pale leg of the five applications.

Dark neurons are observed bilaterally within the dorsal horn of the spinal cord, particularly in sheets I-II, of the rats, 8 days after the ligation of the unilateral sciatic nerve, comparing with the falsely operated rats. Different doses of different compounds of Formula I are tested in this model, and show that the compounds of Formula I reduce both the incidence of dark neurons, and the neuropathic pain behavior in the LCC rats. Having thus described the invention, it will be obvious that it can be varied in many ways. These variations should not be considered as a departure from the spirit and scope of the invention, and it is intended to include all modifications within the scope of the following claims.

Claims (171)

1. NOVELTY OF THE INVENTION Having described the foregoing invention, it is considered as a novelty, and therefore, the content of the following is claimed as property: CLAIMS 1. A compound that inhibits the activity of PARP, and affects a non-neuronal activity. mediated by NMDA toxicity.
2. 2. The compound according to claim 1, characterized in that the neuronal activity is selected from the group consisting of the stimulation of damaged neurons, the promotion of neuronal regeneration, the prevention of neurodegeneration, and the treatment of a neurological disorder.
3. 3. The compound according to claim 2, characterized in that the neurological disorder is selected from the group consisting of peripheral neuropathy caused by physical injury or disease state, traumatic brain injury, physical damage to the spinal cord. , embolism, demyelination disease and neurological disorder related to neurodegeneration.
4. 4. The compound according to claim 3, characterized in that the neurological disorder is embolism.
5. The compound according to claim 3, characterized in that the neurological disorder related to neurodegeneration is selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis.
6. 6. The compound according to claim 1, which forms at least one hydrogen bond with an amino acid of PARP.
7. 7. The compound according to claim 6, characterized in that the amino acid is Gly.
8. 8. The compound according to claim 7, characterized in that said compound contains an NH group that forms a hydrogen bond with the O-atom of Gly.
9. 9. The compound according to claim 8, characterized in that the length of the link is from about 1 to 5 A.
10. 10. The compound according to claim 9, characterized in that the bond length is from about 2 to 4 A.
11. 11. The compound according to claim as claimed in claim 6, characterized in that the amino acid is Ser.
12. 12. The compound according to claim 11, characterized in that this compound contains an atom of O, S, or N, which forms a hydrogen bond with the H atom of Ser.
13. 13. The compound according to claim 12, characterized in that the length of the link is from about 1 to 5A. 1 .
14. The compound according to claim 13, characterized in that the length of the link is from about 2 to 4 Á.
15. 15. The compound according to claim 1, characterized in that this compound has an IC50 to inhibit PARP in vitro of 100 μM or lower.
16. 16. The compound as claimed in claim 15, characterized in that this compound has an IC50 to inhibit PARP in vitro of 25 μM or lower.
17. 17. A compound that inhibits the activity of PARP, and treats or prevents tissue damage resulting from cell death or damage due to necrosis or apoptosis.
18. 18. The compound according to claim 17, characterized in that it further comprises treating or preventing diseases or conditions selected from the group consisting of tissue damage resulting from cell damage or death due to necrosis or apoptosis, tissue damage or diseases mediated by neurons, damage to neural tissue resulting from ischemia and reperfusion injury, neurological disorders and neurodegenerative diseases, vascular embolism, cardiovascular disorders, age-related macular degeneration, AIDS and other diseases of immune senescence, arthritis, atherosclerosis, cachexia, cancer, skeletal muscle degenerative diseases that involve replicative senescence, diabetes, head trauma, immune senescence, inflammatory bowel disorders, muscular dystrophy, osteoarthritis, osteoporosis, chronic pain, acute pain, neuropathic pain, nerve aggression, peripheral nerve injury, renal failure, retinal ischemia, septic shock, and aging of the skin, diseases or disorders related to the life or proliferative capacity of cells, and disease or disease conditions induced or exacerbated by cellular senescence.
19. 19. A pharmaceutical composition comprising: (i) an effective amount of a compound that inhibits PARP activity, and affects a neuronal activity not mediated by NMDA toxicity.; and (ii) a pharmaceutically acceptable carrier.
20. 20. The pharmaceutical composition according to claim 19, characterized in that the neuronal activity is selected from the group consisting of the stimulation of damaged neurons, the promotion of neuronal regeneration, the prevention of neurodegeneration, and the treatment of a neurological disorder.
21. 21. The pharmaceutical composition according to claim 20, characterized in that the neurological disorder is selected from the group consisting of peripheral neuropathy caused by physical injury or disease state, traumatic brain injury, physical damage to the spinal cord, embolism, demyelination disease and neurological disorder related to neurodegeneration.
22. 22. The pharmaceutical composition according to claim 21, characterized in that the neurological disorder is embolism.
23. 23. The pharmaceutical composition according to claim 21, characterized in that the neurological disorder related to neurodegeneration is selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis.
24. 24. The pharmaceutical composition according to claim 19, characterized in that this compound forms at least one hydrogen bond with an amino acid of PARP.
25. 25. The pharmaceutical composition according to claim 24, characterized in that the amino acid is Gly.
26. 26. The pharmaceutical composition according to claim 25, characterized in that said compound contains an NH group that forms a hydrogen bond with the O-atom of Gly.
27. 27. The pharmaceutical composition according to claim 26, characterized in that the bond length is from about 1 to 5A.
28. 28. The pharmaceutical composition according to claim 27, characterized in that the bond length is from about 2 to 4A.
29. 29. The pharmaceutical composition according to claim 24, characterized in that the amino acid is Ser.
30. 30. The pharmaceutical composition according to claim 29, characterized in that said compound contains an O, S, or N, which forms a hydrogen bond with the H atom of Being.
31. 31. The pharmaceutical composition according to claim 30, characterized in that the bond length is from about 1 to 5A.
32. 32. The pharmaceutical composition according to claim 31, characterized in that the bond length is from about 2 to 4 A.
33. 33. The pharmaceutical composition according to claim claimed in claim 19, characterized in that this compound has an IC ^ Q to inhibit PARP in vitro of 100 μM or lower.
34. 34. The pharmaceutical composition according to claim 33, characterized in that this compound has an IC50 to inhibit PARP in vitro of 25 μM or lower.
35. 35. The pharmaceutical composition according to claim 19, characterized in that this compound is present in an amount that is effective to treat a cardiovascular disorder in an animal.
36. 36. The pharmaceutical composition as claimed in claim 35, characterized in that the cardiovascular disorder is selected from the group consisting of coronary artery disease, angina pectoris, myocardial infarction, cardiac arrest, cardiogenic shock, and damage of cardiovascular tissue.
37. 37. The pharmaceutical composition according to claim claimed in claim 19, characterized in that this compound is present in an amount that is effective to treat organ damage due to transplantation.
38. 38. The pharmaceutical composition as claimed in claim 19, characterized in that this compound is present in an amount that is effective to treat an inflammatory bowel disorder in an animal.
39. 39. The pharmaceutical composition according to claim 38, characterized in that the inflammatory disorder of the intestine is Crohn's disease.
40. 40. The pharmaceutical composition according to the claim claimed in claim 38, characterized because the inflammatory disorder of the intestine is colitis.
41. 41. The pharmaceutical composition according to claim claimed in claim 19, characterized in that this compound is present in an amount that is effective to treat arthritis in an animal.
42. 42. The pharmaceutical composition according to claim 19, characterized in that this compound is present in an amount that is effective to treat diabetes in an animal.
43. 43. The pharmaceutical composition according to claim 19, characterized in that this compound is present in an amount that is effective to treat septic shock in an animal.
44. 44. The pharmaceutical composition according to claim 43, characterized in that the septic shock is endotoxic shock.
45. 45. The pharmaceutical composition according to claim 43, characterized in that the septic shock is acute tubular necrosis.
46. 46. The pharmaceutical composition according to claim 19, characterized in that this compound is present in an amount that is effective to treat cancer in an animal.
47. 47. The pharmaceutical composition according to claim 46, characterized in that the cancer is selected from the group consisting of tumors that produce ACTH, acute lymphocytic leukemia, acute non-lymphocytic leukemia, cancer of the adrenal cortex, cancer of the bladder, brain cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia, chronic myelocytic leukemia, colorectal cancer, cutaneous T-cell lymphoma, endometrial cancer, esophageal cancer, Ewing's sarcoma, gallbladder cancer, hairy cell leukemia , head and neck cancer, Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer, liver cancer, lung cancer (small and / or small cells), malignant peritoneal effusion, malignant pleural effusion, melanoma, mesothelioma, multiple myeloma , neuroblastoma, non-Hodgkin's lymphoma, osteosarcoma, ovarian cancer, ovarian cancer (germ cells), cancer pan creat, cancer of the penis, prostate cancer, retinoblastoma, skin cancer, soft tissue sarcoma, squamous cell carcinomas, stomach cancer, testicular cancer, thyroid cancer, trophoblastic neoplasms, uterine cancer, vaginal cancer, cancer the vulva and Wilm's tumor.
48. 48. A pharmaceutical composition comprising: (a) a compound that inhibits the activity of PARP, and treats or prevents tissue damage resulting from cell death or damage due to necrosis or apoptosis; and (b) a pharmaceutically acceptable carrier.
49. 49. The compound according to claim 48, characterized in that it further comprises treating or preventing diseases or conditions selected from the group consisting of tissue damage resulting from cell damage or death due to necrosis or apoptosis, tissue damage or diseases mediated by neurons, neural tissue damage resulting from ischemia and reperfusion injury, neurological disorders, neurological disorders and neurodegenerative diseases, vascular embolism, cardiovascular disorders, age-related macular degeneration, AIDS and other immune senescence diseases, arthritis , atherosclerosis, cachexia, cancer, skeletal muscle degenerative diseases that involve replicative senescence, diabetes, head trauma, immune senescence, inflammatory bowel disorders, muscular dystrophy, osteoarthritis, osteoporosis, chronic pain, acute pain, neuropathic pain, aggression n erviosa, peripheral nerve injury, renal failure, retinal ischemia, septic shock, and aging of the skin, diseases or disorders related to the life or proliferative capacity of cells, and diseases or disease conditions induced or exacerbated by cellular senescence.
50. 50. A method for affecting a neuronal activity not mediated by NMDA toxicity in an animal, which comprises administering an effective amount of a compound that inhibits PARP activity.
51. 51. The method according to claim 50, characterized in that the neuronal activity is selected from the group consisting of the stimulation of damaged neurons, the promotion of neuronal regeneration, the prevention of neurodegeneration, and the treatment of a neurological disorder.
52. 52. The method according to claim 51, characterized in that the neurological disorder is selected from the group consisting of peripheral neuropathy caused by physical injury or disease state, traumatic brain injury, physical damage to the spinal cord. , embolism, demyelination disease and neurological disorder related to neurodegeneration.
53. 53. The method according to claim 52, characterized in that the neurological disorder is embolism.
54. 54. The method according to claim 52, characterized in that the neurological disorder related to neurodegeneration is selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis.
55. 55. The method according to claim 50, characterized in that this compound forms at least one hydrogen bond with an amino acid of the PARP.
56. 56. The method according to claim 55, characterized in that the amino acid is Gly.
57. 57. The method according to claim 56, characterized in that said compound contains an NH group that forms a hydrogen bond with the O-atom of Gly.
58. 58. The method according to claim 37, characterized in that the length of the link is from about 1 to 5 Á.
59. 59. The method according to claim 58, characterized in that the length of the link is from about 2 to 4 A.
60. The method according to claim 55, characterized in that the amino acid is Ser.
61. 61. The method according to claim claimed in claim 60, characterized in that this compound contains an atom of O, S, or N, which forms a hydrogen bond with the H atom of Ser.
62. 62. The method in accordance with the claimed in claim 61, characterized in that the length of the link is from about 1 to 5 A.
63. 63. The method in accordance with that claimed in? 4? claim 62, characterized in that the length of the link is from about 2 to 4 Á.
64. 64. The method according to claim 50, characterized in that this compound has an IC ^ Q to inhibit PARP in vitro of 100 μM or lower.
65. 65. The method according to claim 64, characterized in that this compound has an IC5Q to inhibit PARP in vitro of 25 μM or lower.
66. 66. A method for the treatment of a cardiovascular disorder in an animal, which comprises administering to the animal an effective amount of a compound that inhibits PARP activity and affects a neuronal activity not mediated by NMDA toxicity.
67. 67. The method according to claim 66, characterized in that this compound forms at least one hydrogen bond with an amino acid of the P7ARP.
68. 68. The method according to claim 67, characterized in that the amino acid is Gly.
69. 69. The method according to claim 68, characterized in that said compound contains an NH group that forms a hydrogen bond with the Gly O atom.
70. 70. The method according to claim claimed in claim 69, characterized in that the length of the link l42 is from about 1 to 5 Á.
71. 71. The method according to claim as claimed in claim 70, characterized in that the length of the link is from about 2 to 4 Á.
72. 72. The method according to claim claimed in claim 67, characterized in that the amino acid is Ser.
73. 73. The method according to claim 22, characterized in that this compound contains an atom of O, S, or N, which forms a hydrogen bond with the H atom of Ser.
74. 74. The method according to claim claimed in claim 73, characterized in that the link length is from about 1 to 5 Á.
75. 75. The method according to claim 24, characterized in that the length of the link is approximately 2 to 4 Á.
76. 76. The method according to claim 66, characterized in that this compound has an IC50 to inhibit PARP in vitro of 100 μM or lower.
77. 77. The method according to claim 76, characterized in that this compound has an IC50 to inhibit PARP in vitro of 25 μM or lower.
78. 78. The method according to claim claimed in claim 66, characterized in that the cardiovascular disorder is selected from the group consisting of coronary artery disease, angina pectoris, myocardial infarction, cardiac arrest, cardiogenic shock, and damage of cardiovascular tissue.
79. 79. A method for the treatment of organ damage due to transplantation in an animal, which comprises administering to the animal an effective amount of a compound that inhibits PARP activity and affects a neuronal activity not mediated by NMDA toxicity.
80. 80. The method of compliance with the claim in claim 79, characterized in that this compound forms at least one hydrogen bond with an amino acid of the PARP.
81. 81. The method according to claim claimed in claim 80, characterized in that the amino acid is Gly.
82. 82. The method according to claim 81, characterized in that said compound contains an NH group that forms a hydrogen bond with the O-atom of Gly.
83. 83. The method according to claim 82, characterized in that the length of the link is from about 1 to 5 Á.
84. 84. The method according to claim as claimed in claim 83, characterized in that the length of the link is from about 2 to 4 Á.
85. 85. The method according to claim 84, characterized in that the amino acid is Ser.
86. 86. The method according to claim claimed in claim 85, characterized in that this compound contains an atom of O, S, or N, which forms a hydrogen bond with the H atom of Ser.
87. 87. The method according to claim claimed in claim 86, characterized in that the length of the link is from about 1 to 5 Á.
88. 88. The method according to claim claimed in claim 87, characterized in that the length of the link is from about 2 to 4 Á.
89. 89. The method according to claim claimed in claim 79, characterized in that this compound has an IC ^ Q to inhibit PARP in vitro of 100 μM or lower.
90. 90. The method according to claim claimed in claim 89, characterized in that this compound has an IC50 to inhibit PARP in vitro of 25 μM or lower. *
91. 91. A method for the treatment of an inflammatory bowel disorder in an animal, which comprises administering to the animal an effective amount of a compound that inhibits PARP activity and affects a neuronal activity not mediated by NMDA toxicity.
92. 92. The method according to claim claimed in claim 91, characterized in that this compound forms at least one hydrogen bond with an amino acid of 1 to 5 PARP.
93. 93. The method according to claim 92, characterized in that the amino acid is Gly.
94. 94. The method according to claim claimed in claim 93, characterized in that said compound contains an NH group that forms a hydrogen bond with the 0-atom of Gly.
95. 95. The method according to claim claimed in claim 94, characterized in that the length of the link is from about 1 to 5 A.
96. The method according to claim claimed in claim 95, characterized in that the length of the link is approximately 2 to 4 Á.
97. 97. The method according to claim 92, characterized in that the amino acid is Ser.
98. 98. The method according to claim claimed in claim 97, characterized in that this compound contains an atom of O, S, or N, which forms a hydrogen bond with the H atom of Ser.
99. 99. The method in accordance with the claimed in claim 98, characterized in that the length of the link is from about 1 to 5 Á.
100. 100. The method according to claim claimed in claim 99, characterized in that the link length is from about 2 to 4 A.
101. 101. The method according to claim 91, characterized in that this compound has an IC5Q to inhibit PARP in vitro of 100 μM or lower.
102. 102. The method according to claim 10, characterized in that this compound has an IC50 to inhibit PARP in vitro of 25 μM or lower.
103. 103. The method according to claim claimed in claim 91, characterized in that the inflammatory disorder of the intestine is Crohn's disease.
104. 104. The method according to claim claimed in claim 91, characterized in that the inflammatory disorder of the intestine is colitis.
105. 105. A method for the treatment of arthritis in an animal, which comprises administering to the animal an effective amount of a compound that inhibits PARP activity and affects a neuronal activity not mediated by NMDA toxicity.
106. 106. The method according to claim 105, characterized in that this compound forms at least one hydrogen bond with an amino acid of PARP.
107. 107. The method according to claim 106, characterized in that the amino acid is Gly.
108. 108. The method according to claim 107, characterized in that said compound contains an NH group that forms a hydrogen bond with the Gly O atom.
109. 109. The method according to claim 10, characterized in that the length of the link is from about 1 to 5 A.
110. 110. The method according to claim 10, characterized in that the length of the link is approximately 2 to 4 Á.
111. 111. The method according to claim 10, characterized in that the amino acid is Ser.
112. 112. The method according to claim 111, characterized in that this compound contains an atom of 0, S, or N, which forms a hydrogen bond with the H atom of Ser.
113. 113. The method according to claim 112, characterized in that the length of the link is from about 1 to 5 A.
114. The method according to claim 113, characterized in that the length of the link is approximately 2 to 4 Á.
115. 115. The method according to claim 10, characterized in that this compound has an IC50 to inhibit PARP in vitro of 100 μM or lower.
116. 116. The method according to claim 115, characterized in that this compound has an IC5Q to inhibit PARP in vitro of 25 μM or lower.
117. 117. A method for the treatment of diabetes in an animal, which comprises administering to the animal an effective amount of a compound that inhibits PARP activity and affects a neuronal activity not mediated by NMDA toxicity.
118. 118. The method according to claim 117, characterized in that this compound forms at least one hydrogen bond with an amino acid of PARP.
119. 119. The method of compliance with claiming in claim 118, characterized in that the amino acid is Gly.
120. 120. The method according to claim 119, characterized in that said compound contains an NH group that forms a hydrogen bond with the O-atom of Gly.
121. 121. The method according to claim 120, characterized in that the length of the link is from about 1 to 5 Á.
122. 122. The method according to claim 121, characterized in that the length of the link is from about 2 to 4 Á.
123. 123. The method according to claim 118, characterized in that the amino acid is Ser.
124. 124. The method according to claim 123, characterized in that this compound contains an atom of 0, S, or N, forming a hydrogen bond with the H atom of Ser.
125. 125. The method according to claim 124, characterized in that the link length is from about 1 to 5 A.
126. 126. The method according to claimed in claim 125, characterized in that the length of the link is from about 2 to 4 A.
127. 127. The method according to claim 117, characterized in that this compound has an ICC-Q to inhibit PARP in vitro of 100 μM or lower.
128. 128. The method according to claim 127, characterized in that this compound has an IC50 to inhibit PARP in vitro of 25 μM or lower.
129. 129. A method for the treatment of septic shock in an animal, which comprises administering to the animal an effective amount of a compound that inhibits PARP activity and affects a neuronal activity not mediated by NMDA toxicity.
130. 130. The method according to claim 129, characterized in that this compound forms at least one hydrogen bond with an amino acid of PARP.
131. 131. The method according to claim 130, characterized in that the amino acid is Gly.
132. 132. The method according to claim 13, characterized in that said compound contains an NH group that forms a hydrogen bond with the Gly O atom.
133. 133. The method according to claim 132, characterized in that the length of the link is from about 1 to 5 Á.
134. 134. The method according to claim 13, characterized in that the length of the link is from about 2 to 4 Á.
135. 135. The method according to claim 130, characterized in that the amino acid is Ser.
136. 136. The method according to claim 13, characterized in that this compound contains an atom of O, S, or N, which forms a hydrogen bond with the H atom of Ser.
137. 137. The method in accordance with the claimed in claim 136, characterized in that the length of the link is from about 1 to 5 Á.
138. 138. The method according to claim 137, characterized in that the length of the link is from about 2 to 4 A.
139. 139. The method according to claim 129, characterized in that this compound has an IC ^ Q to inhibit PARP in vitro of 100 μM or lower.
140. 140. The method according to claim 139, characterized in that this compound has an ICCJQ to inhibit PARP in vitro of 25 μM or lower.
141. 141. The method according to claim 129, characterized in that the septic shock is endotoxic shock.
142. 142. The method according to claim 129, characterized in that the septic shock is acute tubular necrosis.
143. 143. A method for treating cancer in an animal, which comprises administering to the animal an effective amount of a compound that inhibits PARP activity and affects a neuronal activity not mediated by NMDA toxicity.
144. 144. The method according to claim 14, characterized in that this compound forms at least one hydrogen bond with an amino acid of the PARP.
145. 145. The method according to claim 14, characterized in that the amino acid is Gly.
146. 146. The method according to claim 14, characterized in that said compound contains an NH group that forms a hydrogen bond with the Gly O atom.
147. 147. The method according to claim 146, characterized in that the length of the link is from about 1 to 5 A.
148. 148. The method according to claim 147, characterized in that the length of the link is from about 2 to 4 A.
149. 149. The method according to claim 14, characterized in that the amino acid is Ser.
150. 150. The method according to claim 149, characterized in that this compound contains a 0, S, or N atom, which forms a hydrogen bond with the H atom of Ser.
151. 151. The method in accordance with the claimed in claim 150, characterized in that the length of the link is from about 1 to 5 Á.
152. 152. The method according to claim 151, characterized in that the length of the link is from about 2 to 4 A.
153. The method according to claim 14, characterized in that this compound has an IC50 for inhibit in vitro PARP of 100 μM or lower.
154. 154. The method according to claim 153, characterized in that this compound has an IC50 to inhibit PARP in vitro of 25 μM or lower.
155. 155. The method according to claim 155, characterized in that the cancer is selected from the group consisting of tumors that produce ACTH, acute lymphocytic leukemia, acute non-lymphocytic leukemia, cancer of the adrenal cortex, cancer of the bladder, brain cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia, chronic myelocytic leukemia, colorectal cancer, cutaneous T-cell lymphoma, endometrial cancer, esophageal cancer, Ewing's sarcoma, gallbladder cancer, hairy cell leukemia, head and neck cancer, Hodgkin lymphoma, Kaposi's sarcoma, kidney cancer, liver cancer, lung cancer (small and / or small cells), malignant peritoneal effusion, malignant pleural effusion, melanoma, mesothelioma, multiple myeloma, neuroblastoma, non-Hodgkin's lymphoma, osteosarcoma, ovarian cancer, ovarian cancer (germ cells), pancreatic cancer, cancer of the penis, prostate cancer, retinoblastoma, skin cancer, soft tissue sarcoma, squamous cell carcinomas, stomach cancer, testicular cancer, cancer thyroid, trophoblastic neoplasms, uterine cancer, vaginal cancer, cancer of the vulva and Wilm's tumor.
156. 156. A method for inhibiting PARP activity, which comprises administering to the animal an effective amount of a compound that inhibits PARP activity and affects a neuronal activity not mediated by NMDA toxicity.
157. 157. The method according to claim 156, characterized in that this compound forms at least one hydrogen bond with an amino acid of the PARP.
158. 158. The method according to claim 157, characterized in that the amino acid is Gly.
159. 159. The method according to claim 158, characterized in that said compound contains a NH group that forms a hydrogen bond with the 0-Gly atom.
160. 160. The method according to claim 159, characterized in that the length of the link is from about 1 to 5 Á.
161. 161. The method according to claim 160, characterized in that the length of the link is approximately 2 to 4 Á.
162. 162. The method according to claim 157, characterized in that the amino acid is Ser.
163. 163. The method according to claim 162, characterized in that this compound contains an atom of O, S, or N, which forms a hydrogen bond with the H atom of Ser.
164. 164. The method in accordance with the claimed in claim 163, characterized in that the length of the link is from about 1 to 5 Á.
165. 165. The method according to claim 24, characterized in that the length of the link is from about 2 to 4 Á.
166. 166. The method according to claim 156, characterized in that this compound has an IC5Q to inhibit PARP in vitro of 100 μM or lower.
167. 167. The method according to claim 166, characterized in that this compound has an ICCyQ to inhibit PARP in vitro of 25 μM or lower.
168. 168. A method for inhibiting PARP activity, which comprises administering an effective amount of a compound that inhibits PARP activity, and treats or prevents tissue damage resulting from cell death or damage due to necrosis or apoptosis.
169. 169. A method for prolonging or increasing the life and proliferative capacity of cells, which comprises administering an effective amount of a compound that inhibits PARP activity.
170. 170. A method for altering the gene expression of senescent cells, which comprises administering an effective amount of a compound that inhibits PARP activity.
171. 171. The compounds, pharmaceutical compositions, methods, and processes described herein.