CZ2000794A3 - Oxo-substituted compounds, process of their preparation pharmaceutical preparations in which said compounds are comprised and methods of inhibiting PARP activity - Google Patents

Abstract

Compounds of formula I containing at least one a ring nitrogen or a pharmaceutically acceptable addition salt thereof base or acid, hydrate, ester, solvate, a prodrug, metabolite, stereoisomer, or mixture thereof wherein: X is a double-bonded oxygen or the group -OH, R7 when present, is a hydrogen atom or a lower alkyl group, Y represents atoms necessary to form a condensed monocyclic, bicyclic or tricyclic, carbocyclic or of a heterocyclic ring, each individual ring contains 5 to 6 ring atoms, and Z is (i) -CHR 2 CHR 3 - wherein R 2 and R 3 are independently hydrogen, alkyl, aryl or aralalkyl, (ii) a group -R 6 C = CR 3 - in which R 3 a R6 independently represent hydrogen, lower alkyl a group, an aryl group, an aralkyl group, a halogen, - NO 2, -COOR 7 or -NR 7 R 8 wherein R 8 is independently a hydrogen atom or a C 1 -C 9 alkyl group, or R 6 and R 3 together they form a fused aromatic ring in which each individual circle contains 5 to 6 members in a circle, (iii) -R 2 C = N-; (iv) -CR 2 (OH) -NR 7 '; or (v) -C (O) -NR 7 -. Further, it is within the scope of the invention pharmaceutical compositions containing these compounds, methods the use of these compounds and methods for preparing such compounds.

Description

Oxo-substituted compounds, processes for their preparation, pharmaceutical compositions containing them and methods for inhibiting PARP activity

Technical field

The invention relates to nucleic acid inhibitors of poles (adenosine-5'-diphospho-ribozo) polymerase [poly (ADP-ribozo) polymerase or PARP, which is also sometimes called PARS for poles (ADP-ribozo) synthetase]. More particularly, the invention relates to the use of PARP inhibitors for the prevention and / or treatment of tissue damage resulting from cell damage or cell death caused by necrosis or apoptosis, nerve tissue damage resulting from ischemia and reperfusion injury, neurological disorders and neurodegenerative diseases, to prevent or to treat stroke, to treat or prevent cardiovascular diseases, to treat other conditions and / or disorders such as macular degeneration associated with aging, AIDS and other immune diseases senescence, arthritis, atherosclerosis, cachexia, cancer, skeletal muscle degenerative diseases including replicative senescence, diabetes, head trauma, immune senescence, inflammatory bowel disease (such as colitis and Crohn's disease), muscular dystrophy, osteoarthritis, osteoporosis, chronic and acute pain (such as neuropathic pain), le dvin, retinal ischemia, septic shock (such as endotoxic shock) and skin aging, to prolong the life span and cell proliferative capacity, to alter senescent cell gene expression or to induce radiation sensitivity in hypoxic tumor cells.

BACKGROUND OF THE INVENTION

Poles (ADPTribozo) polymerase (PARP) is an enzyme located in the nuclei of cells of various organs, including muscle cells, heart and brain cells. PARP has a physiological role in restoring DNA strand breaks. Once activated, the damaged DNA fragments catalyze the attachment of up to 100 ADP-ribose units to a variety of nuclear proteins, including histones and PARP itself. Although the exact range of PARP functions has not yet been fully established, this enzyme is believed to play a role in accelerating DNA repair.

However, during severe cellular stress, extensive activation of PARP can rapidly lead to cellular damage or death through depletion of energy stores. Four ATP molecules are consumed for each newly formed NAD molecule (source of ADP-ribose). Thus, NAD, a PARP substrate, is depleted by massive activation of PARP, and ATP may also be depleted in an attempt to re-synthesize NAD.

It is known from prior art publications that PARP activation plays a key role in both NMDA and NO-induced neurotoxicity, as shown by the use of PARP inhibitors that prevented this toxic effect in cortical cultures in proportion to their ability to inhibit this enzyme (Zhang et al. , Nitric Oxide Activation of Poly (ADP-Ribose) Synthetase in Neurotoxicity, Science, 263, 687-89, 1994), as well as use on sections from the hippocampus (Wallis et al., Neuroprotection Against Nitric Oxide Injury with Inhibitors of ADP- Ribosylation, NeuroReport, 5: 3, 245-48, 1993). Thus, the potential role of PARP inhibitors in the treatment of neurodegenerative diseases and head trauma is known. However, research continues to precisely delineate the exact mechanism of their beneficial effect in cerebral ischemia (9). Endres et al., Ischemic Brain Injury is Mediated by the Activatlon of Poles (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).

One injection of PARP inhibitors has been shown to reduce the size of heart attack caused by ischemia and reperfusion of the heart or skeletal muscle in rabbits. In these studies, a single injection of a PARP 3-aminobenzamide inhibitor (10 mg / kg) given either one minute before occlusion or one minute after reperfusion, caused a similar reduction in the size of myocardial infarction (32-42%). Another PARP inhibitor

1,5-dihydroxyisoquinoline (1 mg / kg) reduced infarct size to a comparable degree (38 to 48%), see Fig. Thiemermann et al.,

Inhibition of the Activity of Poles (ADP-Ribose) Synthetase Reduces Ischemia-Reperfusion Injury in the Heart and Skeletal Muscle, Proc. Nati. Acad. Sci. USA, 94, 679-83,1997). This finding suggested that PARP inhibitors may be able to rescue previously ischemic tissue of the heart or skeletal muscle.

Activation of PARP has also been shown to provide a marker of damage following neurotoxic damage by glutamate (via stimulation of NMDA receptors), reactive intermediate oxygen products, amyloid β-protein, n-methyl-4-phenyl-1,2,3,6 -tetrahydropyridine (MPTP) and its active metabolite N-methyl-4-phenylpyridine (MPP +), which are involved in pathological conditions such as stroke, Alzheimer's and Parkinson's disease (see Zhang et al., Poles (ADP-Ribose) Other studies have continued to investigate the role of PARP activation in cerebellum granules of cells in vitro and the neurotoxicity of MPTP, see, e.g., J. Neurochem., 65: 3, 1411-14, 1995. Cosi et al.,

Poles (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; Cosi et al.,

Poles (ADP-Ribose) Polymerase Inhibitors Protect Against MPTP-induced Depletions of Striatal Dopamine and Cortical Noradrenaline (C57B1 / 6 Mice, Brain Res., 729, 264-69, 1996).

It is believed that nerve damage after stroke and other neurodegenerative processes are due to the massive release of the excitatory neurotransmitter glutamate, which acts on N-methyl-D-aspartate (NMDA) receptors and other receptor subtypes. Glutamate serves as the predominant excitatory neurotransmitter in the central nervous system (CNS). Neurons release glutamate in large quantities when they are deficient in oxygen, which can occur during ischemic brain damage, such as stroke or heart attack. This excessive release of glutamate, in turn, causes excessive stimulation (excitatory toxicity) of N-methyl-D-aspartate (NMDA), AMPA, kainate, and MGR receptors.

When glutamate binds to these receptors, ion channels open at the receptors, allowing ion ions to flow through their cell membranes, e.g., Ca and Na into cells and K out of the cells. These ion fluxes, especially Ca influx, cause excessive neuronal stimulation. Excessively stimulated neurons secrete more glutamate, creating a feedback loop or a domino effect that ultimately results in cell damage or cell death through the production of proteases, lipases, and free radicals. Excessive activation of glutamate receptors results in a variety of neurological diseases and conditions including epilepsy, stroke, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, schizophrenia, chronic pain, ischemia, and neuronal loss after hypoxia, , ischemia, trauma and nerve damage. Recent studies also support the glutamatergic basis of compulsive disorders, especially drug addiction. Evidence includes findings in many animal species, as well as glutamate or NMDA-treated cerebrocortical cultures that glutamate receptor antagonists block neuronal damage following stroke (Dawson et al., Protection of the Brain from Ischemia, Cerebrovascular Disease, 319- 25, H. Hunt Batjer ed., 1997). Attempts to prevent excitotoxicity by blocking N-methyl-D-aspartate (NMDA), AMPA, kainate, and MGR receptors have proven difficult because each receptor has different sites to which glutamate can bind. However, many preparations that are effective in blocking receptors are also toxic to animals. As such, no effective treatment of glutamate abnormalities is known.

Stimulation of NMDA receptors, in turn, activates the enzyme neuronal nitric oxide synthase (NNOS), which causes the formation of nitric oxide (NO), which directly mediates the neurotoxic effect. Treatment with NOS inhibitors protected NMDA neurotoxicity (see Dawson et al., Nitric Oxide Mediates Glutamate Neurotoxicity in Primary Cortical Cultures, Proc. Natl. Acad. Sci. USA, 88, 6368-71, 1991, and Dawson et al., Mechanisms of Nitric Oxide-mediated

4 4 4 4 4 4 4

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44 4,444 9 4 99 9

94 99 44 44 94

Neurotoxicity in Primary Brain Cultures, J. Neurosci.

13: 6, 2651-61 (1993). Protections in cortical cultures from NNOS-targeted mice may also occur against NMDA neurotoxicity (Dawson et al., Resistance to Neurotoxicity in Cortical Cultures from Neuronal Nitric Oxide)

Synthase-Deficient Mice, J. Neurosci, 16: 8, 2479-87 (1996))

Nerve damage after stroke is known to be significantly reduced in animals treated with NOS inhibitors or NNOS gene-deficient mice (see Iadecola, Bright and Dark Sides of Nitric Oxide in Ischemia Brain Injury, Trends Neurosci, 20: 3, 132-39, 1997, 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, 1994). Neither NO or peroxynitrite can cause DNA damage that activates PARP. Further evidence of this is provided by Szabó et al. (DNA Strand Breakage, Activation of Poles (ADP-Ribose) Synthetase, and Cellular Energy Depletion are Involved in the

Cytotoxicity in Macrophages and Smooth Muscle Ceils Exposed to Peroxynitrite, Proc. Nati. Acad. Sci. USA, 93, 1753-58 (1996).

U.S. Patent No. 5,587,384 to Zhang et al., Published Dec. 24, 1996, discloses the use of certain PARP inhibitors, such as benzamide and 1,5-dihydroxyisoquinoline, to prevent NMDA-mediated neurotoxicity and, therefore, to treat cerebrovascular accidents, Alzheimer's disease, Parkinson's disease, and Huntington's disease. However, it has now been discovered that Zhang et al. may be mistaken in classifying neurotoxicity * as NMDA-mediated neurotoxicity. Rather, it might be more appropriate to classify the neurotoxicity present in vivo as glutamate neurotoxicity (Zhang et al., Nitric Oxide Activation of Poly (ADP-Ribose) Synthetase in Neurotoxicity, Science, 263, 687-89, 1994, see also Cosi). et al., Poles (ADP-Ribose) Polymerase Inhibitors Protect Against MTPP-Induced Depletions of Striatal Dopamine and Cortical Noradreanaline (C57B1 / 6 Mice, Brain Res., 729, 264-69, 1996).

It is also known in the art that PARP inhibitors generally affect DNA repair. Cristovao et al. (Effect of a Poly (ADP-Ribose) Polymerase Inhibitor on DNA Breakage and Cytotoxicity Induced by Hydrogen Peroxide and Gamma-Radiation, Terato., Carcino., And Muta., 16, 219-27, 1996) describing the effect of hydrogen peroxide and gamma-ray to DNA strand breaks in the presence and absence of 3-aminobenzamide, a potent PARP inhibitor. Cristovao et al. observed the recovery of PARP-dependent DNA strand breaks in hydrogen peroxide treated leukocytes.

It is also known in the art that PARP inhibitors are capable of inducing radiation sensitivity in hypoxic tumor cells and are able to prevent tumor cells from recovering from potentially lethal DNA damage after radiation therapy, probably due to the ability to prevent DNA repair. See U.S. Patent Nos. 5,032,617, 5,215,738, and 5,041,653.

There is also evidence that PARP inhibitors are useful for the treatment of inflammatory bowel diseases.

Salzman et al. (Role of Peroxynitrite and • · ♦ · · · · ···

Poles (ADP-Ribose) Synthase Activation Experimental Colitis, Japanese J. Pharm., 75, Supp. 1:15, 1997) describes the ability of PARP inhibitors to prevent or treat colitis. Colitis was induced in rats by administration of haptentrinitrobenzenesulfonic acid in 50% ethanol to the intestinal lumen. Treated rats received 3-aminobenzamide, a specific inhibitor of PARP activity. Inhibition of PARP activity reduced the inflammatory response and re-established the morphology and energy state of the distal colon (see also Southan et al., Spontaneous Rearrangement of Aminoalkylithioureas to Mercaptoalkylguanidines, and Novel Class of Nitric Oxide Synthase Inhibitors with Selectivity Towards the Inducible Isoform. J. Pharm., 117, 619-32, 1996, Szab 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).

There is also evidence that PARP inhibitors are useful for the treatment of arthritis. Szabó et al.

(Protect in the Effects of an Inhibitor of

Poles (ADP-Ribose) Synthesis in Collagen-Induced Arthritis, Japanese J. Pharm., 75, Supp. I: 102, 1997) describes the ability of PARP inhibitors to prevent or treat collagen-induced arthritis (see also: Szabo et al., DNA Strand Breakage, Activation of Poles (ADP-Ribose) Synthetase, and Cellular Energy Depletion are Involved in the Cytotoxicity in Macrophages and Smooth Muscle Cells Exposed to Peroxynitrite, Proc Natl Acad Sci USA, 93, 1753-58, March 1996, Bauer et al., Modification of Growth Related Enzymatic Pathways and Apparent Loss of Tumorigenicity of Ras-Transformed Bovine Endothelial Cell Line by Treatment with 5-Iodo-6-amino-1,2-benzopyrone (INL ^ BP), Intl.

♦ · · · · · · «« «« «« «« «« « ·· ·· ·· ·· ·· · ·

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, J. Immuno., 153, 3319-25, 1994 ).

Furthermore, PARP inhibitors appear to be useful for the treatment of diabetes. Heller et al. (Inactivation of Poles (ADP-Ribose) Polymerase Gene Affects Oxygen Radical and Nitric Oxide Toxicity in Islet Cells, J. Biol. Chem.,

270: 19, 11176-80, May 1995) describes the tendency of PARP to deplete cell NAD + and induce the death of insulin-producing islet cells. Heller et al. used cells from mice with inactivated PARP genes and found that these mutated cells did not show NAD + depletion after exposure to DNA damaging radicals. The mutated cells have also been found to be more resistant to NO toxicity.

In addition, PARP inhibitors have been shown to be useful in the treatment of endotoxic 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) reported that inhibition of pole-triggered DNA (ADP-ribose) DNA repair cycle by synthetase has protective effects against vascular failure in endotoxic shock. Zingarelli et al. found that nicotinamide protects against delayed NO-mediated vascular failure in endotoxic shock. Zingarelli et al. have also found that nicotinamide action may be related to the inhibition of the activation of the polio-triggered DNA repair cycle (ADP-ribose) by energy-consuming synthetase, and this inhibition of activation is NO-mediated (see also Cuzzocrea, Role of Peroxynitrite and Activation). T 000 0 0000 0 00 0 “Poles (ADP-Ribose) Synthetase in the Vascular Failure

Induced by Zymosan-activated Plasma, Brit. J. Pharm.

493-503, 1997) Yet another known use of PARP inhibitors is the treatment of cancer. Suto et al. (Dihydroisoquinolinones: Design and Synthesis of a New Series of Potent Inhibitors of Poly (ADP-Ribose) Polymerase, Anticancer Drug Res., 7, 107-17, 1991) discloses methods for synthesizing a variety of different PARP inhibitors. In addition, aw in U.S. Patent No. 5,177,075 to Suto et al. Discloses several isoquinolines used to enhance the lethal effects of ionizing radiation or chemotherapeutic agents on tumor cells. Weltin et al. (Effect of 6 (5H) -Phenanthridione, an Inhibitor of

Polymers (ADP-Ribose) Polymerase, on Cultured Tumor Cells, Oncol. Res., 6: 9, 399-403, 1994) discloses inhibiting PARP activity, reduced tumor cell proliferation, and a pronounced synergistic effect when tumor cells are co-treated with an alkylating agent (drug).

Yet another use of PARP inhibitors is the treatment of peripheral nerve injury and the resulting pathological pain syndrome known as neuropathic pain, such as pain caused by chronic constriction injury (CCI) of the common sciatic nerve, in which transsynaptic alteration of the posterior horns is characterized by hyperchromatosis of cytoplasm and dark neurons) (Mao et al., Pain, 72, 355-366, 1997).

PARP inhibitors have also been used to prolong the lifespan and proliferative capacity of cells, including the treatment of diseases such as skin aging, Alzheimer's disease,

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44 44 44 44 44 atherosclerosis, osteoarthritis, osteoporosis, muscular dystrophy, skeletal muscle degenerative diseases including replication of senerscence, age-related macular degeneration, immune senescence, AIDS and other immune diseases of senescence, and for altering gene expression of senescent cells (see International Patent Publication) application

VO 98/27975).

In Banasik et al. (Specific Inhibitor of Poles (ADP-Ribose) Synthetase and Mono (ADP-Ribosyl) -Transferase, J. Biol. Chem., 267: 3, 1569-75, 1992) and Banasik et al. A large number of known PARP inhibitors have been described (Inhibitors and Activators of ADP-Ribosylation Reactions, Molec. Cell. Biochem., 138, 185-97, 1994).

However, the approach to the use of these PARP inhibitors as discussed above is actually limited. For example, side effects have been observed with some of the best known PARP inhibitors as described by Milam et al. Inhibitors of Poles (Adenosine Diphosphate-Ribose)

Synthesis: Effect on Other Metabolic Processes

223, 589-91 (1984). In particular, PARP inhibitors

3-aminobenzamide and benzamide not only inhibited the effect of PARP, but were also shown to affect cell viability, glucose metabolism and DNA synthesis. Therefore, it has been concluded that the utility of these PARP inhibitors can be severely limited by the difficulty of finding a dose that will inhibit the enzyme without causing further metabolic effects.

From the foregoing, it is apparent that there is a need in the art to develop compounds that inhibit

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00 00 00 00 · 0 PARP activity, pharmaceutical compositions containing the compounds, and methods of using the compounds, wherein the compounds exhibit better and more reliable effects with less side effects compared to previously known compounds and methods of inhibiting PARP activity and treatments and diseases and conditions discussed above.

Various oxo-substituted multi-ring compounds other than the compounds of the present invention are known in the art. These compounds and corresponding references include, but are not limited to, the following list:

AND.

3- (5-Hexinyl) -2,4a, 5,6,7,7a-hexahydro-1H-cyclopenta [c] pyridin-1-one, Rougeot et al., Cyclization Reactions of 2-pentynyl-4- pyrimidinones, J. Heterocycl. Chem., 20: 5,1407-9 (1983);

II.

2,4a, 5,6,7,7a-Hexahydro-3-methyl-1H-cyclopenta- [c] pyridin-1-one, Davies et al., Intramolecular Cycloaddione Reactions of Mono- and

Dihydroxy-pyrimidines, J. Chem. Soc., 11: 1293-97 (1978);

III.

2,4a, 5,6,7,7a-Hexahydro-3-phenyl-1H-cyclopenta- [c] pyridin-1-one, Davies et al., Intramolecular Cycloaddione Reactions of Mono- and

Dihydroxy-pyrimidines, J. Chem. Soc., 11: 1293-97 (1978);

IV.

Octahydro-3-methyl-1 (2H) -isoquinolinone, Ochiai et al., Polarization of Heterocyclic Rings with Aromatic Character. CXLVII. Reaction of 3-Methyl-5,6,7,8-tetrahydroisoquinoline-2-oxide with Acetic Anhydride, Itsuu Kenkusho Nempo, 16: 15-23 (1971);

• 999 • 9 9

99 quinolin-4-one, 1,2,3,4-tetrahydro-7 (or 9) -methyl-4H-cyclopenta [c] quinoline-4-one, and 1,2,3,5-tetrahydro-4H- cyclopenta [c] quinolin-4-one, see:

(a) Brown et al., Reaction of Ethyl 2-0xocyclopentanecarboxylate with Arylamines. Part I. The Preparation of 2,3-dihydro-.alpha.-quinindones (2,3,4,5-tetrahydro-4-oxo-1H-cyclopenta [c] quinolines), J. Chem. Soc., 4295-98 (1961);

(b) 1,2,3,5-Tetrahydro-4H-cyclopenta- [c] quinoline-4-one, Reisch, Chemistry of Natural Substances. VII. Furoquinoline Derivatives By Condensation Of Ethyl 2-Propynyl Malonate With Aromatic Amines, Arch. Pharm. Ber. Dtsch. Pharm. Ges., 300: 6, 533-39 (1967);

(c) 1,2,3,5-Tetrahydro-4H-cyclopenta- [c] quinoline-4-one, Eisch et al., Studies on Nonpyridinoid Azaaromatic Systems. 7. Synthesis and Tautomeric Character of

Cyclopenta [c] quinoline (benzo [c] [2] pyrindine), J. Org. Chem., 43: 11, 2190-96 (1978);

(d) 1,2,3,5-Tetrahydro-4H-cyclopenta- [c] quinoline-4-one, Castan et al. , New Arylpiperazine Derivatives with High Affinity for 5-HT 1 Receptor Sites, Med. Chem. Res., 6: 2, 81-101 (1996);

(e) 1,2,3,5-Tetrahydro-4H-cyclopenta- [c] quinoline-4-one;

Reid et al., Reactions of Cyclic Enamines. III. Synthesis of N-Heterocycles from Cycloalkenylamine isocyanate or isothiocyanate Adducts, Ann. Chem., 688: 177-88 (1965); and (f) 1,2,3,5-Tetrahydro-4H-cyclopenta [c] quinoline-4-one, Reid et al., Reactions with Cyclic Enamines. I. Reaction of Cycloalkene-amines with Phenyl Isocyanate and Phenylisothiocyanate, Ann., 673: 132-36 (1964);

IX

2-Hydroxy-3,4-cyclopentenoquinoline, Johnson, The Synthesis of N-Alkyl-2-Oxocyclopentane-Carboxyamides;

• · · · · · · · ·

J. Chem. Soc., 1624-28 (1958);

X.

1,2,4,6-Tetrahydro-5H-thiopyrano [3,4-c] quinolin-5-one, Castan et al., New Arylpiperazine Derivatives with High Affinity for 5-HT 1 Receptor Sites, Med. Chem. Soc., 6: 2, 81-101 (1996);

XI.

6a, 7,8,9,10,10a-Hexahydro-trans-6 (5H) -phenanthridinone, see:

(a) Masamune et al., Condensed Polynuclear Perhydro Compounds Containing Nitrogen. XII. Synthesis and Exhaustive Methylation of 5,6,6a, 7,8,9,10,10a-0-octahydrophenanthridines and Related Compounds, J. Org. Chem.,

29: 3, 681-85 (1964);

(b) 6α, 7,8,9,10,10α-Hexahydro-cis (+) 6 (5H) -phenanthridinone, Naito et al., Asymmetric Photocyclization of Na., β-Unsaturated Acylanilides Heterocycles, 22: 2, 237 -40 (1984), along with the (6aR-trans) - and (6aS-trans) - stereoisomers of the same compound;

(c) Michailidis et al., Hexahydrogenated Derivatives of Phenanthridone Obtained by Birch Reaction, C.R. Acad.

Sci., 275: 17, 961-64 (1972), with cis and trans stereoisomers of the same compound;

(d) Ninomiya et al., Photocyclization of Enamides. V. Photocyclization of α, β-Unsaturated Anilides, J. Chem. Soc., 1:14, 1747-51 (1974), with the cis stereoisomer; and (e) Taylor et al., Phenanthridine Syntheses Via the

Diels-Alder Reaction. And New Routes do it

6 (5) -Phenanthridinone, J. Am. Chem. Soc., 78: 5104-8 (1956);

XII.

7,8,9,10-Tetrahydro-65 (Η), see:

(a) Masamune et al., The Synthesis and Exhaustive · «esis ·« «« «« am am am am am am am am am am am am am · ·· ·· ·

Methylation of 5,6,7,8,9,10,6a, 10a-O-octydrophenanthridines and Related Compounds, J. Org. Chem., 29: 3,

681-85 (1964) Γ (b) Bailey et al., Reactions of p-Toluenesulfonyl Azide with Derivatives of Cyclohept- and Cyclooctindole, J. Chem. Soc., 1: 7, 763-70 (1974);

(c) Reid et al., Reactions of Cyclic Enamines. III. Synthesis of N-Heterocycles from Cycloalkenylamine isocyanate or isothiocyanate Adducts, Ann. Chem., 688: 177-88 (1965); and (d) Reid et al., Reactions with Cyclic Enamines. AND.

Reaction of Cycloalkene-amines with Phenyl Isocyanate and Phenylisothiocyanate, Ann., 132-36 (1964); and

XIII.

1,2,3,3a, 5,9b-Hexahydro-cyclopenta [c] quinolin-4-one, Blount et al., Stereoisomerism in Polycyclic Systems. Part VI., I. Chem. Soc., 1979, 1984 (1929).

1,2,3,5-Tetrahydrocyclopenta [c] quinolin-4-one, see Castan et al., New Arylpiperazine Derivatives with High Affinity for 5-HT 3 Receptor Sites, Med. Chem. Res., 6: 2, 81-101 (1996), is an intermediate of the process for the preparation of novel high affinity arylpiperazine derivatives for serotoninergic S3 receptor sites, with respect to structure. However, it is not anticipated, nor is it known from the prior art, that this intermediate or any other of the above-cited oxo-substituted compounds could inhibit PARP activity.

Other oxo-substituted compounds are listed in the following publications:

(1) Taylor et al., Phenanthridine Syntheses Via the Diels-Alder Reaction. A New Route's to • 4 4 4 9 9 »

4,444 4,444

94,444 94 4

4 «4» 48

4 4 «

6 (5) -Phenanthridinone, J. Am. Chem. Soc., 78: 5104-8 (1956);

(2) Reid et al., Reactions of Cyclic Enamines. III. Synthesis of N-Heterocycles from Cycloalkenylamine-isocyanate or -isothiocyanate Adducts, Ann. Chem., 688: 177-88 (1965);

(3) Gauthier, U.S. Patent No. 3,838,134, which discloses phenanthridinone compounds used as antiviral agents; and (4) Vinter et al., U.S. Patent No. 4,382,943, which discloses anti-allergic aryl ether derivatives.

Other structurally different compounds have also been proposed for medical and other uses. For example, U.S. Pat.

No. 4,382,943 (Vinter et al.), Which discloses the use of dibenzo- [b] [d] pyran-6-one as an antihistamine, as an anti-edema agent, and as an anti-inflammatory agent.

U.S. Patent No. 4,169,897 to Meyer et al. Entitled 2,7-Bis-Basic Ethers of 9-Phenanthrol and 9-Loweralkoxy Phenanthrol discloses certain phenanthrenes and phenanthrinidinones which are useful in preventing or inhibiting viral infections.

United States Patent No. 4,082,741 (Hunger et al.) Entitled Disazo Pigments Derived from 3,8-Diamino-Phenanthridinone- (10) discloses compounds that are useful as pigments and can therefore be used for preparation of printing inks, color lakes and dispersion inks, which are used for dyeing rubber materials, plastic materials and natural or synthetic resins. In the United States Patent. No. 3,291,801 (Montgomery) discloses certain octahydro-6 (S) -phenanthridinones which can be converted to the corresponding 6 (S) -phenanthridinones which are useful as intermediates for the preparation of therapeutically active compounds. U.S. Patent No. 3,507,872 to Hegar entitled Indolyl-Quinolinium Dyestuffs discloses water-soluble basic dyes containing α-pyridones and gamma-pyridones.

U.S. Patent No. 5,274,097 to Schohe discloses a variety of 1,3-di-substituted pyrrolidines which may be substituted, inter alia, by the following group:

these structures are reported to have a high affinity for cerebral 5-hydroxytryptamine receptors of the 5-HT1-type known to combat diseases recognizable by disorders of the serotoninergic system, in particular related to receptors with high affinity for 5-hydroxytryptamine ( 5-HTp typ.

SUMMARY OF THE INVENTION

It has now been found that certain selected oxo-substituted PARP inhibitors can be used to treat or prevent tissue damage resulting from cellular damage or death caused by necrosis or apoptosis, and these the compounds may ameliorate nerve tissue damage, including damage that occurs following focal ischemia and reperfusion injury. In general, inhibition of PARP activity saves the cell from energy loss, prevents irreversible depolarization of neurons and thus provides neuronal protection. Notwithstanding the foregoing, it is believed that activation of PARP may, in addition to the formation of free radicals and nitric oxide, also have a general role in other excitatively toxic mechanisms not yet discovered.

The present invention relates to compounds of formula I containing at least one ring nitrogen:

(I) or a pharmaceutically acceptable base or acid addition salt, hydrate, ester, solvate, prodrug, metabolite, stereoisomer or mixture thereof, wherein:

X is a double bonded oxygen or -OH,

R, when present, represents a hydrogen atom or a lower alkyl group,

Y represents the atoms necessary to form a fused monocyclic, bicyclic or tricyclic, carbocyclic or heterocyclic ring, each ring containing 5 to 6 atoms as ring members, and

Z is (A) --CHR3 CHR3 - in which R3 is

and i is in the meta-position and R is in the ortho-position with respect to said ring nitrogen of formula I, and R and R are independently hydrogen, hydroxy, amino, dimethylamino, nitro, piperidine, piperazine, imidazolidine , an alkyl group, an aryl group or an aralkyl group, (ii) a group - r 6c = Cr 3 - in which R 1 is in the meta position with respect to the ring nitrogen;

and R ^J and R nezávisle are each independently hydrogen, lower alkyl, aryl, aralkyl, halogen, hydroxy, amino, dimethylamino, piperidine, piperazine, imidazolidine, -NC> 2, -COOR? or -NR 2 R ³ , wherein R ³ is independently hydrogen or C 1 -C 9 alkyl, or R 0 and R ³ together form a fused aromatic ring in which each ring contains 5 to 6 members in the ring; (iii) a-RC = N- group;

(iv) -CR 1 (OH) -NR 2 -;

(v) a -C (O) -NR 7 - group, or (vi) an -NR 9 -C (O) -CH 2 R 10 - group, in which R 10 is in the ortho position to the ring nitrogen, and

R ⁹ and R ¹⁰ independently of one another are hydrogen, lower alkyl, aryl, aralkyl, halogen, hydroxy, piperidine, piperazine, imidazolidine, -NO 2 -, -COOR? or a group -NR? R ^ in which R?

• 0 ·

• · 0

• 00

independently represents a hydrogen atom or an alkyl group having 1 to 9 carbon atoms, or R 10 together form a fused ring wherein each individual ring contains 5 to 7 ring members, said alkyl, aryl and aralkyl group being substituted on one or more positions by hydrogen, hydroxy, halogen, haloalkyl, alkoxy, alkenoxy, alkaryloxy, aryloxy, arylalkoxy, cyano, amino, imino, sulfhydryl, thioalkyl, alkyl, lower-alkyl, carbocyclic, lower-carbocyclic, a cycloalkyl group, an aryl group, an arylalkyl group, a haloaryl group, an amino group, a nitro group, a nitro group, a dimethylamino group, with the following conditions:

(a) when X is a double bonded oxygen,

And Z is -CHR CHR-, then R cannot be hydrogen or methyl, (b) when X is a double bonded oxygen, and Z is -R ^ C = CR · ^ -, then R cannot be a methyl group, a phenyl group or a group

- (ch ₂ ) ₄ -c = ch, (c) when R 2 and R 2 together form a fused aromatic ring Y cannot be a ring selected from the group consisting of:

9 9 9 9 9 9 9 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

- 22 - * ·· ** ·· * *. ♦ ** ·· * ’* · ··

(d) when X, Y and Z together form a phenanthridone, phenanthridinone, phenanthrene or phenanthridine core with an amino or aminoalkoxylene group at the 3-position, then the 8-position cannot also be substituted with an amino or aminoalkoxylene group; and (e) where X is a double bonded oxygen, and Z is a six membered unsaturated ring, and Y is a phenyl group, then the 2-position of the Z-ring cannot be substituted by hydrogen or nitro, (f) when X is -OH or oxygen with a double bond, and Z is -CH = CH-, then Y is not a phenyl or 5-hydroxyphenyl group, (g) when X is a double bonded oxygen, and Z is -CH = N-, then Y is not a phenyl group, and (h) when X is a double bonded oxygen, then Z is a -C (O) NH- group, then Y is not an aminophenyl group.

The present invention also provides a process for the preparation of compounds of formula (I) as defined above, comprising the step of contacting an intermediate of formula (IV):

(IV) wherein Y and Z have the same meaning as previously defined, with a nitrogen introducing agent to form a compound of formula V:

(IN)

In a further aspect, the present invention relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula I containing at least one ring nitrogen:

(AND)

9 9 9 9 ·· 9999

9 99 9 9999

99 9 9 99

Or a pharmaceutically acceptable base or acid addition salt, hydrate, ester, solvate, prodrug, metabolite, stereoisomer or mixtures thereof, in which:

X is a double bonded oxygen or -OH,

R ', if present, represents a hydrogen atom or a lower alkyl group,

Y represents the atoms necessary to form a fused monocyclic, bicyclic or tricyclic, carbocyclic or heterocyclic ring, each ring containing from 5 to 6 ring atoms, and

Z is (i) -CHR 1 CHR 1 -, wherein R 1 is a

in the meta-position and R is in the ortho-position with respect to said

The ring nitrogen of formula (I), and R and R are independently hydrogen, hydroxy, amino, dimethylamino, nitro, piperidine, piperazine, imidazolidine, alkyl, aryl or aralkyl, (ii) - R ^C ^R ^ - - in which R ^ is in the meta position relative to the ring nitrogen, and R R and R ° independently of one another are hydrogen, lower alkyl, aryl, aralkyl, halogen, hydroxy, amino , dimethylamino, piperidine, piperazine, imidazolidine,

-NC> 2, -COOR? or a group -NR 4 R ® in which R ® independently represents a hydrogen atom or an alkyl group containing 1 to carbon atoms,

A -2 or R ° and R ^J together form a fused aromatic ring in which each individual ring contains 5 to 6 ring members, 4 4 444 4 4 44 4 4 4 · 4 · 4 · 4 ·· 4

(Iii) -R ² C = N-;

(iv) -CR ² (OH) -NR ⁷ -;

(v ^ -C (O) -NR ⁷ -, or (vi) -Nr 9 -C (O) -CHr 10 - in which R 4 -θ is ortho to the ring nitrogen, and

R ⁹ and R ¹⁰ independently represent hydrogen, lower alkyl, aryl, aralkyl, halogen, hydroxy, piperidino group, piperazino group, imidazolidine group, -NO2-, -COOR ⁷ or -NR ⁷ R Wherein R 6 independently represents a hydrogen atom or a C 1 -C 9 alkyl group, or R ⁹ and R 6 together form a fused ring wherein each individual ring contains 5 to 7 ring members, said alkyl group, aryl and aralkyl are substituted at one or more positions by hydrogen, hydroxy, halogen, haloalkyl, alkoxy, alkenoxy, alkaryloxy, aryloxy, arylalkoxy, cyano, amino, imine, sulfhydryl, sulfocyclyl, thioalkyl , lower alkyl, lower alk alkyl, cycloalkyl, aryl, arylalkyl, haloaryl, amino, nitro, nitro, dimethylamino, with the following conditions:

(a) when X is a double bonded oxygen, o and a and Z are -CHR CHR -, then R cannot be a hydrogen atom or a methyl group (b) when X is oxygen with a double bond, and Z is -R ^ C = CR ^ -, then R ^ cannot be methyl, phenyl or a group

- (ch ₂ ) ₄ -c = ch, (c) when R ^J and R 0 together form a fused aromatic ring Y cannot be a ring selected from the group consisting of:

(d) when X, Y and Z together form a phenanthridone, phenanthridinone, phenanthrene or phenanthridine core with an amino or aminoalkoxylene group at the 3-position, then the 8-position cannot also be substituted with an amino or aminoalkoxylene group; and (e) where X is a double bonded oxygen, and Z is a six membered unsaturated ring, and Y is a phenyl group, then the 2-position of the Z-ring cannot be substituted by hydrogen or nitro, (f) when X is -OH or oxygen with a double bond, and Z is -CH = CH-, then Y is not a phenyl group or a 5-hydroxyphenyl group, (g) when X is a double bonded oxygen,

0 • 0 ·· • 0 • 00 • · 0 0 0 ·· 000 00 0 0000 0000 0000 00 00 00 00 00 00 00 and Z is -CH = N-, then Y is not phenyl, and (h) v when X is a double bonded oxygen, then Z is -C (O) NH-, then Y is not an aminophenyl group.

In a further aspect, the present invention relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula I containing at least one ring nitrogen:

NR / (I) or a pharmaceutically acceptable base or acid addition salt, hydrate, ester, solvate, prodrug, metabolite, stereoisomer or mixtures thereof, wherein:

X is a double bonded oxygen or -OH,

R, when present, represents a hydrogen atom or a lower alkyl group,

Y represents the atoms necessary to form a fused monocyclic, bicyclic or tricyclic, carbocyclic or heterocyclic ring, each ring containing from 5 to 6 ring atoms, and

Z is (i) a group -CHR 2 CHR 2 - in which it is in the meta-position and R is in the ortho-position with respect to said

9 9 4 4 4 4 4 9 4 ··

44 44 44

Ovému ring nitrogen in formula I, and R a are independently hydrogen, hydroxy, amino, dimethylamino, nitro, piperidine, piperazine, imidazolidine, alkyl, aryl or aralkyl, (ii) -R 6c = CR 3 -, in which R 1 is in the meta position relative to the ring nitrogen, 3 and R ⁵ and R ⁵ independently represent a hydrogen atom, a lower alkyl group, an aryl group, an aralkyl group, a halogen, a hydroxy group, an amino group , a dimethylamino group, a piperidine group, a piperazine group, an imidazolidine group, a -NO2, -COOR ⁷ group or a -NR ⁷ R ® group in which R ® is independently hydrogen or an alkyl group having 1 to 9 carbon atoms, or R ° and R ^J together form a fused aromatic ring wherein each single ring contains 5 to 6 ring members, (iii) -R ² C = N-;

(iv) -CR ² (OH) -NR ⁷ -;

(v) -C (O) -NR ⁷ -, or (vi) a group -NR 9 -C (O) -CHrIO-, which is in the ortho-position to the ring nitrogen, and

Rl® R₁ and independently represent hydrogen, lower alkyl, aryl, aralkyl, halogen, hydroxy, piperidino group, piperazino group, imidazolidine group, -NO2-, -COOR ⁷ or -NR ⁷ R ® in which R 6 independently represents a hydrogen atom or an alkyl group containing 1 to 9 carbon atoms, or R 6 and R 6 together form a fused ring in which each individual ring contains 5 to 7 ring members;

00 ·

Wherein said alkyl, aryl and aralkyl groups are substituted at one or more positions by hydrogen, hydroxy, halogen, haloalkyl, alkoxy, alkenoxy, alkaryloxy, aryloxy, arylalkoxy, cyano, amino, thio, imino, imino, imino, imino, imino a carboxy group, a carbocyclic group, a heterocyclic group, a lower alkyl group, a lower alkenyl group, a cycloalkyl group, an aryl group, an arylalkyl group, a haloaryl group, an amino group, a nitro group, a nitro group, a dimethylamino group, and a compound of formula I is present in an amount sufficient inhibit PARP activity, treat or prevent tissue damage resulting from cell damage or death caused by necrosis or apoptosis, affect neuronal activity not mediated toxic effects of NMDA, affect neuronal activity not mediated by toxic effects of NMDA, treat nerve tissue damage resulting from ischemia and reperfusion injury, neurological disorders and neurodegenerative diseases, prevent or treat stroke, treat or prevent cardiovascular disease, treat other conditions and / or diseases such as age-related macular degeneration, AIDS and other immune diseases senescence, arthritis, atherosclerosis, cachexia, cancer, skeletal muscle degenerative diseases including replicative senescence, diabetes, head trauma, immune senescence, inflammatory bowel diseases (such as colitis and Crohn's disease), muscular dystrophy, osteoarthritis, osteoporosis, 0 00 0 0 0 0 0 0 0 0 0 0 0 · 0 0 0 0 0

0 0 0

00 chronic and / or acute pain (such as neuropathic pain), renal failure, retinal ischemia, septic shock (such as endotcutic shock) and skin aging, prolong life expectancy and cell proliferation capacity, alter senescent cell gene expression or induce radiation sensitivity in hypoxic tumor cells.

In another aspect, the present invention includes a method of inhibiting PARP activity comprising administering a compound of formula I as defined above in connection with the description of the pharmaceutical compositions of the invention. According to another embodiment of the invention, the amount of the compound administered in the methods of the invention is sufficient to treat tissue damage resulting from cell damage or cell death caused by necrosis or apoptosis, nerve tissue damage due to ischemia and reperfusion injury or neurological disorders and neurodegenerative diseases, for the prevention or treatment of stroke, for the treatment or prevention of cardiovascular disease, for the treatment of other conditions and / or disorders such as age-related macular degeneration, AIDS and other immune diseases senescence, arthritis, atherosclerosis, cachexia, cancer, skeletal muscle degenerative diseases including replication senescence, diabetes, head trauma, immune senescence, inflammatory bowel disease (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 skin aging, to extend the life span and cell proliferation capacity, to alter gene expression of senescent cells, or for radiosensitization (sensitivity to radiation) of hypoxic tumor cells.

Fefe fefe fefe ffe fc f I fefefe fefe fefe fefe fefe fefe fefe fefe fefe fefe fefe fefe fefe fefe fefe fefe fefe fefe fefe fefe fefe fefe fefe fefe

Description of attached pictures

Figure 1 shows the cross-sectional area distribution of infarct at representative sites along the rostrocaudal oxy, measured from the interaurea line in untreated animals and in animals treated with 10 milligrams / kilogram of 3,4-dihydro-5- [4- (1-piperidinyl) butoxy] - 1 (2H) -isoquinolinone.

Figure 2 shows the effect of intraperitoneal administration of 3,4-dihydro-5- [4- (1-piperidinyl) butoxy] -1 (2H) -isoquinolinone on infarct volume.

The oxo-substituted compounds of the present invention as defined above often act as PARP inhibitors.

As such, the compounds can be used to treat or prevent nerve tissue damage due to cellular damage or death due to necrosis or apoptosis, cerebral ischemia and reperfusion injury or neurodegenerative diseases in animals, further extending life expectancy and proliferative capacity In addition, the compounds may alter the gene expression of senescent cells and may induce radiation sensitivity (radiosensitization) in hypoxic tumor cells. Preferably, the oso-substituted compounds of the present invention can be used to treat or prevent tissue damage that results from cell damage or death caused by necrosis or apoptosis and / or by neuronal activity mediated or not mediated by NMDA toxic action. These oso-substituted compounds of the invention are believed to interfere in more events than it is

- 32 ······································ Biological pathways possible these neurotoxic effects of glutamate and NO mediated. Further, the oxo-substituted compounds of the present invention can be used to treat or prevent other tissue damage related to PARP activation.

For example, the oxo-substituted compounds of the present invention can be used to treat or prevent cardiovascular tissue damage resulting from cardiac ischemia or reperfusion injury. Reperfusion injury occurs, for example, at the end of an operation such as cardiac bypass or during cardiac arrest when a heart that has not previously received blood begins to reperfuse.

The oxo-substituted compounds of the present invention can also be used to prolong or increase the life span or cell proliferation and thus treat or prevent the diseases associated with it and are induced or exacerbated by cellular senescence such as skin aging, atherosclerosis, osteoarthritis, osteoporosis, muscular dystrophy, skeletal muscle degenerative diseases including replication senescence, age-related macular degeneration, immune senescence, AIDS and other immune senescence diseases, and other diseases related to cellular senescence and aging, as well as altering gene expression of senescent cells. These compounds can also be used to treat cancer and to induce radiation sensitivity (radiosensitization) in hypoxic tumor cells by making the tumor cells more sensitive to radiation therapy, thereby preventing the tumor cells from recovering from potentially lethal DNA damage after radiation therapy, probably due to the ability to prevent DNA repair. The compounds of the present invention can be used for 9 9 ft. 9 9 preventing or treating a stroke, treating or preventing cardiovascular disease, treating other disease states and / or diseases such as age related macular degeneration, AIDS and other immune diseases senescence, arthritis, atherosclerosis, cachexia, cancer, skeletal degenerative diseases muscles including replicative senescence, diabetes, head trauma, immune senescence, inflammatory bowel disease (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 skin aging.

The oxo-substituted compounds of the invention can treat or prevent further tissue damage that may occur in relation to PARP activation. These compounds are believed to interfere with the more than neurotoxic action of glutamate and NO-mediated biological pathways. Preferably, these oxo-substituted compounds of the invention exhibit an IC 50 for inhibition of PARP in vitro of about 100 μΜ or less, more preferably about 25 μΜ or less. Preferably, the oxo-substituted compounds of the invention affect neuronal activity not mediated by toxic NMDA.

The compounds of the invention preferably act as inhibitors of PARP and can therefore be used to treat or prevent tissue damage resulting from cell death or damage caused by necrosis or apoptosis, to treat or prevent nerve tissue damage due to cerebral ischemia and reperfusion injury or neurodegenerative diseases in the animal, to prolong or increase the life span or cell proliferation and thereby treat or prevent diseases which:

0 0 φ 0 000 · ·· · φ φφ 0 · 0 · · ·

0000 000®

Φ0 0 0 · · ·· ·

0 0 • · ··

0 0

0 0 ♦ · are associated with and are induced or exacerbated by cellular senescence such as skin aging, atherosclerosis, osteoarthritis, osteoporosis, muscular dystrophy, skeletal muscle degenerative diseases including replication senescence, age-related macular degeneration, immune senescence, AIDS and other immune diseases of senescence, and other diseases associated with cellular senescence and aging, as well as to alter gene expression of senescent cells. These compounds can also be used to treat cancer and to induce radiation sensitivity (radiosensibiliation) in hypoxic tumor cells by making the tumor cells more receptive to radiation therapy and preventing the tumor cells from recovering from potentially lethal damage DNA after radiation therapy, probably due to the ability to prevent DNA repair. They can also be used to treat or prevent chronic pain, acute pain, neuropathic pain, renal failure, cachexia, or retinal ischemia. These compounds are believed to interfere with more than the neurotoxic effects of NMDA and NO-mediated biological pathways. Preferably, the compounds of the invention exhibit an IC 50 for inhibition of PARP in vitro of about 100 µΜ or less, more preferably about 25 µΜ or less.

The compounds of the present invention have the general formula I:

• ·· · • about 9 9 ·

9 9 a

Wherein: X is a double bonded oxygen or group

-OH-. According to a particularly preferred embodiment, X is double bond oxygen

When R is present, it represents a hydrogen atom or a lower alkyl group. Examples of such lower alkyl groups for R are: methyl, ethyl, isopropyl, tert-butyl, n-pentyl and n-hexyl, but are not limited thereto. Preferably R is hydrogen.

In the above general formula (I), the substituent Y represents the atoms necessary to form a fused 5- or 6-membered or aromatic or non-aromatic, carbocyclic or heterocyclic ring. The carbocyclic moieties include alicyclic and aromatic structures. When Y forms a fused five-membered carbocyclic ring, examples of such moieties include cyclopentane, cyclopentene or cyclopentadiene condensed nuclei.

When Y is a 5-membered heterocyclic ring, examples are fused pyrrole, isopyrrole, imidazole, isoimidazole, pyrazole, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, isothiazole, isoxazole, furazan, furan, furan, furan, furan, furan , 2,3-triazole,

1,2,4-triazole, dithiol, oxathiol, isoxazole, oxazole, thiazole, isothiazole, oxadiazole, oxatriazole, dioxazole, oxathiazole and the like other ring structures.

* · · · · · · · · · · · · · · · · · · · · ·

9 9

9 999

9 9 ·

9 9 9

99

When Y is a six-membered carbocyclic ring, examples of such moieties include fused cyclohexane, cyclohexene or benzene rings optionally substituted with other fused rings to form, for example, naphthalene, anthracene, phenanthrene, benzonaphthene, and the like. When Y is a six membered heterocyclic ring, examples are pyridine, pyrazine, pyrimidine, pyridazine, pyran, pyronic, dioxin, piperidine, piperazine, morpholine, triazine, oxazine, isoxazine, oxathiazine or oxadiazine ring and the like systems.

Preferably, however, Y contains at least one unsaturated site. More preferably, Y represents the atoms necessary to form a fused or naphthalene ring. Further, Y may form an unsubstituted or substituted system with a non-hydrogen substituent not adversely affecting the nature of this moiety.

Optionally present substituents of the Y moiety include substituents that do not adversely affect the reaction and objectives of the present invention. Examples of such substituents include, but are not limited to, straight or branched chain alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl , tert-butyl, n-pentyl,

2-methylpentyl, 2-methylhexyl, dodecyl, octadecyl and the like, and straight or branched alkenyl groups

0

0

0 0 «β 0 00

0 0 0

0 0 0

A chain such as ethenyl, propenyl, butenyl, pentenyl, 2-methylpentenyl, vinylisopropenyl,

2,2-dimethyl-1-propenyl, decenyl, hexadecenyl and the like, as well as straight or branched chain alkynyl groups such as ethynyl, propynyl, butynyl, pentinyl, hexinyl, heptinyl, octinyl and the like, cycloalkyl groups such as cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like, cycloalkenyl groups such as cyclopropenyl a cyclopentadienyl group, a cyclohexenyl group, a cyclooctenyl group and the like, and aralkyl groups such as benzyl, 3- (1) -naphthyl-1-propyl, p-halobenzyl, p-ethylbenzyl,

1-phenyl-1-propyl, 3-pyridinyl-1-propyl 1-phenyl-2-sec-butyl,

4-phenyl-4-methyl-1-pentyl and the like; aryl groups such as phenyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, indolyl, isoindolyl, indolinyl, benzofuranyl, benzothiophenyl, indazolyl, benzamidazolyl, benzathiazolyl, tetrahydrophthiazolyl a group, tetrahydropyranyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl,

9 9 9 •

9 98 9 • 9 9 9 9 9

99 9 9 9 9 9 9 99 9 9 99 99 99 99 9 99 99 tetrahydroquinolinyl, quinolizinyl, furyl, thiophenyl, imidazolyl, oxazolyl, benzoxazolyl, thiazolyl, isoxazolyl, isotriazolyl, oxadiazolyl, oxadiazolyl triazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, thienyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, pthyrrididinyl, acetyrididinyl, pthyrridinyl, pthyridinyl a phenazinyl group, a phenothiazinyl group, a phenoxazinyl group, and the like; alkoxy groups such as methoxy, ethoxy, sec-propoxy, tert-butoxy, pentoxy, nonoxy and the like; alkenoxy groups such as ethenoxy groups,

2-propenoxy, 3-butenoxy,

2,2-dimethyl-3-butenoxy, 1-hexenoxy,

3-octenoxy, 2-nonenoxy and the like; aryloxy groups such as phenoxy, naphthoxy, pyridinoxy and the like; further aralkyloxy such as benzyloxy, 1-naphthyl-2-ethoxy and the like; alkanoyl groups such as formyl, acetyl, propanoyl, butanoyl, pentanoyl, benzoyl and the like; haloalkyl groups such as trifluoromethyl; non-aromatic heterocyclic groups; and other groups such as hydroxy, carboxy, carbonyl, amino, alkylamino, amide, cyano, isocyanate, nitro, nitro, nitrile, isonitrile, imine, azo, diazo, sulfonyl a group, sulfoxy, SO 3 K, thio, thiocarbonyl, alkylthio, sulfhydryl, halogen and the like.

Optional substituents on the above-mentioned aryl groups may be any substituents which do not adversely affect the nature of these groups. However, preferred substituents include, but are not limited to, alkyl, alkenyl, alkoxy, phenoxy, benzyloxy, cycloalkyl, cycloalkenyl, hydroxy, carboxy, carbonyl, amino, amide, cyano, nitro, nitro, nitro, nitro, nitro, nitro, nitro, nitro, nitro, nitro, nitro, isonitrile, imino, azo, diazo, sulfonyl, sulfoxy, thio, thiocarbonyl, sulfhydryl, halogen, haloalkyl and aryl.

Preferably, when Y is a substituted group with a non-hydrogen and non-interfering substituent, the substituent is selected from the group consisting of -NO ₂ , halogen such as chloro or bromo, -OR 4, or a group -NHR 4 in which R 5 represents a hydrogen atom or a lower alkyl group.

According to another preferred embodiment, Y is an optionally substituted group with a non-interfering substituent that bridges two or more fused rings.

0 0 0 • ·· • 0 0 «00 0 0 0 ·· 0000 0000 0 00 00 00 00 ·· of this compound. Such a compound may have, for example, a tetracyclic structure of the general formula:

wherein V is -O-, -S-, -NR ¹ , -CHO, -CHOH or -CHNH 2 wherein R ¹ is hydrogen or lower alkyl. In a preferred embodiment, R ¹ is a lower alkyl group as specified above.

In a particularly preferred embodiment, the compound of the present invention has the tetracyclic bridging structure of ring Y of the following general formula:

in which :

V is -CH-, is hydrogen, hydroxy or amino, and

X2 represents a hydrogen atom, an amino group, a 1-piperidine group, a 1-piperazine group, a 1-imidazolidine group or a hydroxy group.

4 · 4

In another preferred embodiment, Y may be a substituted group with two or more non-hydrogen substituents which together form an additional fused five or six membered ring, such as a fused cyclopentyl, cyclopentadiene, benzene, cyclohexene or cyclohexene ring.

The substituent Z in the general formula I can represent:

(i) -CHR ² CHR ³ -, (ii) -R ⁽ 'C = CR ^3' ), (iii) -R ² C = N-;

(iv) -CR ² (OH) -NR ⁷ -;

(v) a -C (O) -NR ⁷ - group, (vi) an -NR ⁹ -C (O) -CH 2 -Q- group in which R 6 is ortho to the ring nitrogen.

In a preferred embodiment of the invention Z is -CHR ² CHR ² -, -R ⁶ C = CR ³ or -R ² C = N-.

o o

When Z is -CHRCHR-, 3 R is located in the meta-position and R is located in the ortho position relative to the location of the ring nitrogen in formula I. C = CR ³ -, then the substituent R ³ is located in the meta position to the ring nitrogen.

3 Q 1)

The substituents R, R, R and R in groups (i) to (vi) above may independently be hydrogen, hydroxy, amino, dimethylamino, nitro, alkyl, such as methyl, ethyl, isopropyl, tert-butyl, n-pentyl, sec-octyl, dodecyl and the like;

4

4 4 • 4 4 4 • 4

44

4 4

44

44

4 4 4

44 an aryl group such as a phenyl group, a piperidine group, a piperazine group and an imidazolidine group, or an aralkyl group such as a benzyl group, 1-naphthylmethyl group and a p-halo-benzyl group.

In the group of formula (ii) (-R 1 C = CR 1 -), R 1 and R ^{3 may} independently be hydrogen, hydroxy, alkylamino, dimethylamino, lower alkyl as specified above, aryl as specified above, an aralkyl group as specified above, a halogen such as chloro and bromo, -NO 2, -COOR? or -NR R. When R is -NR'R °,

O then R is independently hydrogen or alkyl of 1 to 9 carbon atoms. By way of example, suitable alkyl groups containing 1 to 9 carbon atoms

O for R is, without limitation, methyl, ethyl, isopropyl, tert-butyl, n-pentyl, n-hexyl, heptenyl, sec-octyl and nonyl. In the advantageous

However, in an embodiment of the invention, R 0 is a lower alkyl group as specified above.

Alternatively, R 1 and R 2 may be joined to form a fused aromatic, monocyclic, bicyclic or tricyclic carbocyclic or heterocyclic ring, wherein each individual ring has 5 to 6 members as ring atoms. Examples of such rings include a fused pyrrole group, an isopyrrole group, an imidazole group, an isoimidazole group, a triazole group, a pyrazole group, a pyridine group, and a pyridine group.

99, a thiophene, a furan, a thiazole, an isothiazole, an oxazole, an isoxazole, an oxadiazole, a benzene, a naphthalene, an acridine, a pyran, a pyron, a pyrazine, a pyrimidine , pyridazine or triazine. When Z represents a group -R 6c = Cr 3 -, in which R 1 and R 2, taken together, form a fused aromatic ring, the ring thus formed is preferably substituted by one or more non-hydrogen non- interfering substituents as specified above for Y. Particularly preferred substituents are selected from the group consisting of halogens such as chloro and bromo, amino and nitro.

In the case of the compounds of the present invention, the multicyclic ring structure formed by Y and Z is preferably one of the following structures:

1,2-dihydroixoquinoline

1,2-dihydrophthalazine

3,4-dihydropteridine

3,4-dihydroquinazoline · * • 9 9 • · ♦ ·

4 4

4 9 ··

44 ·· ··

4 4 9 4 4 * • 4 ··· 9 9 9 ·. · · 444 44 4

44 99 99

1,2-dihydropyrido [3,4b] pyridine

1,2-dihydropyrido [4,3b] pyridine

1,2-dihydropyrazino [2,3d] pyridazine

1,6-dihydropurine

bridge structure

5,6-dihydrophenanthridine in which V is as defined above, or a pharmacologically acceptable base or acid addition salt, prodrug, metabolite, stereoisomer or mixtures of these structures. Preferably, the compound of formula (I) of the present invention has the isoquinoline, pteridine, phenanthridine, phthalazine or quinazoline core having the tetracyclic bridging structure shown above. According to a most preferred embodiment, the compound of the present invention has a phenanthridine core.

The following specific examples of oxo-substituted compounds of formula I, which are set forth in Table I below, are illustrative of suitable embodiments of the compounds of the present invention, and are not intended to limit the scope of the invention.

TABLE I

compound C. X Y of 1 _r C -ch ₂ -ch ₂ - 2 0 -ck-ch _2-1 AND 1 ch ₃ 3 OH -ch-ch ₂ -I 1 and_ 1 ch ₂ 4 —Ch-ch ₂ - 9 and II lf IL_ c _s H _s

99 99

9

9999 9 9 • 9 9 9 9 9

9

99 ··

TABLE I (continued)

compound no. X Y of 5 r and / _ -ce-ch _2-1 c ₄ E ₅ 6 1 -ch-ch ₂ - 1 ch _{2 -} c ₄ h ₅ 7 r -CH-CK, - 1 ch ₂ -c _s k ₅ 8 H N 11_ -ch-ch ₂ - 1 CH / CH ₃ ch ₃ 9 r H xN. N !] _ -ch-ch ₂ -CH ₃ CH ₃ ch ₃ 10 1 H ιΛ N- -ck-ch ₂ - ch _{3 -} c-ch ₃ 1 ch ₃ 11 _r H N- -CH-CH ₃ - 1 ch ₃ -c-ch ₃ 1 ch ₃

• 0 • 00

0 0 <00 00 »0 0 <0 0 00

TABLE I (continued)

compound C. X Y of 12 1 H íl · - C = CH! CaHj 13 r H íl · - C = CH 1 c ₂ h ₅ 14 < Ř H N II N- - C = CH - 1 C · E _S 15 Dec H n ' ⁿ - II N- - C = CH 1 C _with H _s 16 N 11_ - C = CH - C ₃ -C ₄ H _s 17 OH N ] - C = CH - and CH ₂ -C _s phi ₅ 13 N- - C = CH - 1 Cl

9 9 1

11 1

10 1

01

9 9 • 9 91

Φ 9 · «• 0 9 ·« * · · ···· 0 9 ·

1 00

TABLE I (continued)

compound C. X Y of 19 Dec r 1 7 - C = CH - 1 Cl 20 May F C - C = CH - 1 Br 21 r C - C = CH - ! Br 22nd and C - C = CH 1 nh-c ₂ h ₅ 23 r C - C = CH 1 nh-c ₂ h ₅ 24 F C - CH ₂ = N - 25 _r C - CH ₂ = N -

• • 99 99 99 99 99 99 · 9 9 9 9 9

TABLE I (continued)

compound no. X Y of 26 F C - C = N - 1 CH / CH ₃ CH ₃ 27 Mar: r 0 - C = N 1 CH / CH ₃ CH ₃ 23 t - 'CH - NH - 1 CH 29 r C' - CH - NH 1 CH 30 and N IN 0 31 r N IN ÍÓ 32 Ϊ - CO - NH -

• 9

9 9 9 9 9 9 9 9 99 9 9 9 9 999 9 9

99 9 9 9 9 9

9 99 9 9 «9 9« 99

TABLE I (continued)

compound C. X Y of 33 he - CO - NH - 1 34 P - CO - N | II CzHj 35 ? ^H - CO - N - 1 C ₂ H ₅ 36 F r Sr IN 37 r 0 at 38 1 Ř N 1 at 39 he N 1 in at

0 0 0 0 0 0 0 1 0 00 00 C0 00 ··

TABLE I (continued)

compound no. X Y of 40 and r ⁰ · / b 41 r _r ° - 'ύ 42 F << ⁿ << / - - CH - CH - 43 OH C - CK ₂ - CH 44 r C You 45 r C You 4 o and C -AND Y Br

······· · · ··· · · ··· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · »« · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

TABLE I (continued)

compound C. X Y of 47 r C 7 Br 48 and 9 NO: AND", 49 _r 9 NO: 50 Ϊ 9- / 0 51 r 9 with- 'φ Br 52 ϊ C 9 no ₂

• 44

4

4 4 4 • 4 <· «4 41 44

TABLE I (continued)

compound C. X Y of 53 and C Ý COOH 54 r C hive 55 ϊ ₂ nc ₂ 56 r 9 no ₂ -j 57 F C IN ČOOCHj 53 C J COOCH3

4

4

4 44 «4 44 44»

4 • 44

TABLE I (continued)

compound C. X Y of - 59 F C Cl 60 he Γ ' 1 1 in Cl 61 and AND in Ťl 'Cl 62 he 1 to/ O '01 63 Ϊ C Br ^ NOj

• 9

44

4 · 44 «>

TABLE I (continued)

compound  C. X Y i ...... ...... ri, OF 64 r C Br 65 F C - C = CH - CH ₂ H _S 66 r C - C = CH - 1 E _N K ₅ 67 and - CH = CH - 68 _r r - CH = CH -

• 00 00 00 00 00 00 00

00 000 00 000 00 0 • 0 0 0 0 ·

TABLE I (continued)

• 9 • 9

0 · · · · ·

The present invention also includes pharmacologically acceptable base addition salts or acid addition salts, hydrates, esters, solvates, prodrugs, metabolites, stereoisomers or mixtures thereof.

Particularly preferred compounds listed in Table I above are those with numbers 46, 48, 50, 52, 59, 61, 63, 69 and 71. The most preferred compounds of this class of compounds are those of the present invention with number 59.

Another preferred group of compounds of formula (I) of the present invention are those listed in Table II below.

• • • •

· · · * * * * * * * * * * * * * * * * * * * ·

TABLE II (continued)

X Y of Structure of Compound i Ϊ clay -C = CH- 1 CH 3 -C 1 CH 2 Cl 2 H 5 t C -CH = N | <° Y% ^c H3

0 9 11

Another example of preferred compounds of the present invention are those of the following general formula, which are specified in greater detail in Table III below.

TABLE III

^R 1 ^R 2 ^R 3 ch ₃ Cl F ch ₃ H F ch ₃ no ₂ F nh ₂ Cl F nh ₂ no ₂ F nh ₂ Cl H nh ₂ Cl no ₂ nh ₂ H F nh ₂ ch ₃ H no ₂ H F no ₂ no ₂ F OH Cl F OH no ₂ F Br H F Br no ₂ H

9

99

9

999

A further example of a preferred class of compounds of the present invention are those of the following general formula, which are specified in Table IV below.

9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9

9 9 9 ·· · · 9 9 9 9

TABLE IV

^R 2 ^R 3 Cl H H F H no ₂

Another example of a preferred class of compounds of the present invention are those of the following general formula, which are specified in Table V below.

444 • 4 • 44

44 444 44 444

44 4 4 44 4 4 44 • 44 44 44 44 44

TABLE V

^R 1 ^R 2 H H H nh ₂ H 1-piperidine H 1-piperazine H 1-imidazolidine H OH OH H OH nh ₂ OH 1-piperidine OH 1-piperazine OH 1-imidazolidine OH OH nh ₂ H nh ₂ nh ₂ nh ₂ 1-piperidine nh ₂ 1-piperazine nh ₂ 1-imidazolidine nh ₂ OH

0

00 ··· 0 0 0 0 0 0 0 00 00 00 00 00 00 00

The compounds of the present invention have one or more asymmetric centers and, in view of the above, can be prepared as mixtures of (racemic and non-racemic) stereoisomers or as individual enantiomers or diastereomers. These individual stereoisomers may be obtained by optically active starting materials followed by resolution of the racemic or non-racemic mixture of the intermediate in one of the appropriate phases of the synthesis process or by resolution of the compound of formula (I).

The term isomers refers to compounds having the same number and type of atoms and hence the same molecular weight, but differing in the arrangement or configuration of the atoms. Stereoisomers are isomers that differ only in the way the atoms are arranged in space. Enantiomers are a pair of stereoisomers that represent a non-overlapping mirror image of one another. Diastereoisomers are stereoisomers that are not mirror images of one another. Racemic mixture means a mixture containing equivalent portions or roughly equivalent portions of the individual enantiomers. A non-racemic mixture is a mixture containing non-equivalent proportions of individual enantiomers or stereoisomers.

The compounds of the present invention may be preferred in their free base form, in the form of pharmaceutically acceptable salts, in the form of pharmaceutically acceptable hydrates, in the form of pharmaceutically acceptable esters, in the form of pharmaceutically acceptable solvates, in the form of pharmaceutically acceptable prodrugs, in the form of acceptable metabolites and in the form of pharmaceutically acceptable stereoisomers. All these forms • 0 • ·· • 000

0 0 00 0 0 0 0 0 0 0 00 00 00 00 00 is within the scope of the present invention. In practical application, the use of these forms does not differ from the neutral compounds.

By a pharmaceutically acceptable salt, hydrate, ester or solvate is meant a salt, hydrate, ester or solvate of a compound of the present invention that exhibits the desired pharmacological activity and which is neither biologically nor otherwise unacceptable. For the preparation of salts, hydrates, esters or solvates such as acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, p-toluenesulfonate, hydrogensulfate, sulfamate, sulfate, naphthylate, butyrate, citrate, camphate, camphorsulfonate, cyclopentane propionate, digylsulfonate , ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, tosylate and undecanoate, organic acids may be used to prepare organic acids such salts, hydrates, esters or solvates such as hydrochloride, hydrobromide, hydroiodide and thiocyanate.

Examples of suitable basic salts, hydrates, esters or solvates are ammonia-derived hydroxides, carbonates and bicarbonates, alkali metal salts such as sodium salts, lithium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, aluminum salts and zinc salts.

These salts, hydrates, esters or solvates may also be prepared with organic bases. Among the suitable organic bases which are preferred for the preparation of pharmaceutically acceptable base addition salts are:

9 • 9

99 hydrates, esters or solvates derived from the compounds of the present invention include those which are non-toxic and strong enough to prepare such salts, hydrates, esters or solvates. By way of illustration, a group of organic bases include mono-, di- and trialkylamines such as methylamine, dimethylamine, triethylamine and dicyclohexylamine, mono-, di-, or trihydroxyalkylamines such as monoethanolamine, diethanolamine and the like. triethanolamine, amino amino acids such as arginine and lysine, guanidine, N-methylglucosamine, N-methylglucamine, L-glutamine, N-methylpiperazine, morpholine, ethylenediamine,

N-benzylphenethylamine, (trihydroxymethyl) aminoethane and the like. Reference may be made, for example, to Pharmaceutical Salts, J. Pharm. Sci., 66: 11-11 (1977). Accordingly, the nitrogen-containing basic groups can also be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl and butyl chloride, bromide and iodide, diethyl, dibutyl and diamyl sulfate long chain halides such as decyl, lauryl, myristyl and stearyl chloride, bromide and iodide, and aralkyl halides such as benzyl and phenethyl bromide.

Said acid addition salts, hydrates, esters or solvates of said basic compounds may be prepared either by dissolving the free base form of the PARP inhibitor in an aqueous or aqueous alcoholic solution or in another suitable solvent containing the appropriate acid or base, followed by separating the salt by evaporating the solution. Alternatively, the free base form of said PARP inhibitor may be reacted with an acid.

0 00 0 0 00 00 and also react this acid-containing PARP inhibitor with a base, these reactions taking place in an organic solvent, in which case the salt is separated directly or can be obtained by concentrating the solution.

The term pharmaceutically acceptable prodrug is a mini derivative of a compound of the present invention that undergoes biotransformation before its pharmacological effect (s) occur. This prodrug is formulated for the reason (s) to achieve better chemical stability, improved patient acceptance and compliance, better bioavailability, longer duration of action, better organ selectivity, better formulation quality (such as increased formulation). hydrosolubility and / or suppression of side effects (such as toxicity) This precursor (or prodrug) can be readily prepared from the compounds of the invention using methods known in the art such as those described in Burgers Medicinal Chemzstry and Drug Chemzstry, (5th Ed., Vol. 1, 172-178, 949-982, 1995) For example, the compounds of the invention can be transformed into prodrugs by converting one or more hydroxy or carboxy groups to esters.

The term "pharmaceutically acceptable metabolite" refers to drugs that have undergone metabolic transformation. Upon entry into the body, most drugs are a substrate for chemical reactions that can alter their physical properties and biological effects. These metabolic conversions, which usually affect the polarity of the compound, alter the way drugs are distributed and excreted in the body. However, in some 9

9 99 99 999

9 9 9 9 9 9 9 9 9 9 9 9 · 9 9 9 9 9

99 99 99 99 99 drug metabolism is essential for therapeutic effect. For example, antimetabolite class anti-cancer drugs must be converted to their active forms after they have been transported to the cancer cell. Because drugs have to undergo some metabolic transformation, the biochemical reactions that play a role in drug metabolism can be numerous and diverse. The major site of drug metabolism is the liver, although other tissues may also be involved.

A characteristic feature of many of these transformations is that metabolic products are more polar than the parent drugs, although a polar drug sometimes provides a less polar product. Substances with high lipid / water partition coefficients that easily cross membranes also easily diffuse from tubular urine through tubular kidney cells back to plasma. Thus, these substances tend to have low renal clearance and long persistence in the body. If the drug is metabolized to a more polar compound with a lower partition coefficient, its tubular reabsorption will be greatly reduced. In addition, specific secretion mechanisms for anions and cations in proximal renal tubules and in liver parenchyma cells activate highly polar substances.

A specific example is phenacetin (acetophenetidine) and acetanilide, which are both mild analgesic and antipyretic agents, but each transforms in the body into the more polar and more potent metabolite p-hydroxyacetanilide (acetaminophen), which is widely used today. When a patient is given a dose of acetanilide, subsequent metabolites progressively peak in plasma and breakdown in plasma. During the first hour, it is the major component of plasma

4 94 49 44 49 44 acetanilide. In the second hour, as the acetanilide level decreases, the concentration of acetaminophen metabolites peaks. Finally, after a few hours, the major component of plasma is another metabolite that is inert and can be expelled from the body. Thus, the plasma concentration of one or more metabolites as well as the concentration of the drug itself may be pharmacologically important.

The reactions that take place during drug metabolism are often classified into two groups, as shown in Table VI below. Phase I reactions (or functionalization) are usually composed of:

(1) oxidation and reduction reactions in which new functional groups are changed and formed; and (2) hydrolytic reactions in which esters and amides are cleaved to form masked functional groups.

These changes occur in the direction of increased polarity.

Phase II reactions are usually conjugated reactions in which the drug, or often a metabolite of the drug, is added to an endogenous substrate such as glucuronic acid, acetic acid, or sulfuric acid.

4 · 44

4 · * ·

· ·

TABLE VI

Phase I reaction (functionalization reaction) (1) oxidation by hepatic microsomal system P450:

aliphatic oxidation aromatic hydroxylation N-dealkylation

O-dealkylation

S-dealkylation epoxidation oxidative deamination sulfoxide formation desulfuration

N-oxidation and N-hydroxylation of dehalogenation (2) Oxidation via non-microsomal mechanism:

oxidation of alcohol and aldehyde purine oxidation of oxidative deamination (monoamine oxidase and diamine oxidase) (3)

azo and nitro reduction (4)

Ester and Amide Hydrolysis Peptide Bond Hydrolysis Epoxy Hydration

TABLE VI (continued)

Phase II reaction (conjugation reaction):

(1) glucuronidation (2) acetylation (3) mercapturic acid formation (4) sulphate conjugation (5) N-, O- and S-methylation, (6) trans-sulfuration

The compounds of Formula I as inhibitors used in the compositions of the present invention typically exhibit an IC 50 value for inhibiting the in vitro (ADP-ribozo) polymerase polymerase of 100 μΜ or less, and more preferably 10 μΜ or less.

Synthesis of compounds of the invention

Many compounds that inhibit PARP activity can be synthesized by known methods of the prior art using starting materials which are known or commercially obtainable, or can be prepared by methods used to prepare the corresponding similar compounds known and known in the art. See, for example, Suto et al.

Dihydroisoquinolinones: Design and Synthesis of a New Series of Potent Inhibitors of Poles (ADP-Ribose) Polymerase, Anticancer Drug Des., 7: 107-17 (1991), which describes a process for preparing a variety of different PARP inhibitors.

Preferred building blocks for the synthetic preparation of compounds of formula I in which X is a double bonded oxygen are phenanthridinones. By way of example, the (5H) -phenanthridin-6-one compounds of the invention can be prepared by reacting a compound of formula IV:

(IV) with a nitrogen introducing agent such as a combination of NaN 4 and H 2 SO 4 to give a compound of formula V:

For example, to prepare (5H) -phenanthridin-6-one from the starting fluoren-9-one, the Schmidt method can be used in a conventional manner, as illustrated below:

9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9

9 9 9 9 9 9 9 9 9 9

9 9 9 9 9 9 9 9 9 9

fluoren-9-one 5 (R) -phenanthridin-6-one

In this exemplary procedure, fluoren-9-one is generally substituted. These fluoren-9-one starting derivatives are well known in the chemical literature and are generally obtainable by methods known to those skilled in the art. Phenanthridinones can also be prepared by an intramolecular Heck reaction analogous to the procedure of Chide et al. Tetrahedron Lett., 32: 35, 4525-28 (1991).

Other methods that can be used to prepare the compound of the invention are set forth in the following publications, but are not limited thereto:

I. The Smith reaction of Respondly et al., Acad. Sci. Paris, Ser. C, (1967);

II. The photocyclization method described in Ninomiya et al., Tetrahedron Lett., 4451 (1970) and Ichiya et al. J. Chem. Soc., 1: 2257 (1973);

III. The isocyanate intramolecular cycloaddition reaction can be found, for example, in the following publications:

• 0 · • ·

0 0

00 ··

0 0 0 0

0 0 0 β · ·

(a) Balazs et al., Synthesis, 1373 (1995)); 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, 577-9 (1986).

The aforementioned publications serve as reference materials here. Other variations and modifications to the synthetic procedures described in these publications will be apparent to those skilled in the art.

Pharmaceutical preparations

Another aspect of the present invention is directed to a pharmaceutical composition which is also within the scope of the present invention, comprising a pharmaceutically acceptable carrier or diluent and a compound of Formula I or a pharmaceutically acceptable salt, prodrug, metabolite, stereoisomer or mixtures thereof derived from said compound. (referred to herein as a compound of Formula I). Preferably, the compound of formula I is present in an amount effective to inhibit PARP activity.

The compounds of formula (I) of the present invention are suitable for the preparation of pharmaceutical compositions comprising an effective amount of the compound in conjunction with or in admixture with excipients or carrier materials suitable for either enteral or parenteral administration. The compositions of the present invention are per se suitable for oral administration, and may be in the form of discrete units such as capsules, cachets, tablets, dragees, or candies, each containing a predetermined amount of the active ingredient, or in the form of a powder or granules, or 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.

The formulation is usually formulated in a suitable unit dosage form such as a tablet, capsule, aqueous suspension or solution. Said formulations generally comprise a solid, semi-solid or liquid carrier. Examples of such carrier materials include lactose, corn starch, dextrosis, sucrose, sorbitol, mannitol, starches, acacia resin, calcium phosphate, mineral oil, cocoa butter, alginates, tragacanth, gelatin syrup, methylcellulose, polyoxyethylene sorbitan monohydrate, propyl, methylhydroxybenzoate, propyl, methylhydroxybenzoate, propylene, talc, magnesium stearate and the like.

Preferably, the compositions are in the form of tablets and gelatin capsules which contain the active ingredient together with (a) diluents, such as lactose, dried corn starch, dextrosis, sucrose, mannitol, sorbitol, cellulose and the like. and / or glycine, and / or (b) lubricants, such as silica, talc, stearic acid, magnesium and calcium salts thereof, and polyethylene glycol.

These tablets may also contain a filler such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose or polyvinylpyrrolidone. If desired, these tablets may also contain disintegrants such as starches, agar resin, alginic acid or its sodium salt, or effervescent mixtures, and / or absorbents, colorants, flavoring agents and sweeteners. Aqueous suspensions may contain emulsifying and suspending agents combined with the active ingredients. Oral dosage forms may also further contain sweetening and / or flavoring agents and / or coloring agents.

These compositions may be sterilized and / or adjuvants such as preservatives, stabilizers, swelling or emulsifying agents, solubilizing promoters, salts for regulating the osmotic pressure and / or buffering agents may be added. In addition, the compositions may also contain therapeutically active agents. These compositions may be prepared by conventional methods known in the art, by mixing, granulating or coating methods.

• • • •·· 9 0 9 9 9 9 0 0

9 0 9 9 9 9 9 1 1 0 0

1 10 0 9 0 0 19 1 ·

A tablet may be formed by compressing or molding the active ingredient as desired with one or more accessory ingredients. Compressed tablets may be prepared in a suitable machine by compressing the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surfactant or dispersing agent as appropriate. Compressed tablets may be formed in a suitable machine by compressing a mixture of the powdered active ingredient and a suitable carrier material moistened with an inert liquid diluent.

When administered by the parenteral route, the composition of the present invention is usually in unit dosage form, in the form of a sterile injectable preparation (aqueous isotonic solution, suspension or emulsion) in combination with a pharmaceutically acceptable carrier. Such carriers include, but are not limited to, nontoxic, parenterally acceptable, non-therapeutic diluents or solutions. Examples of such carriers include water, aqueous solutions such as saline (isotonic sodium chloride solution), Ringier's solution, dextrose solution, and Hanks' solution, and non-aqueous carriers such as e.g.

1,3-butanediol, fixed non-drawing oils (such as corn oil, cottonseed oil, peanut oil, sesame oil and synthetic mono- or di-glyceride oil), ethyl oleate and isopropyl myristate.

The oily suspensions may be formulated using methods and techniques known in the art using suitable dispersing or wetting agents and suspending agents. Among these acceptable solvents

9

9 9

9

9

9 9 * 99 • 99,999 99,999 99 9

9999 9999 9999 • 9 99 99 99 99 99 or suspending media include sterile, fixed oils. For this purpose any bland, non-irritating, fixed oil may be employed. Fatty acids such as oleic acid and its glyceride derivatives, including olive oil and castor oil, may also be used in the preparation of injectables, particularly in their polyoxyethylated forms. These oily solutions or suspensions may also contain long-chain alcohols as diluents or dispersants.

Preferably a sterile saline solution is used as the carrier material, and the compounds used are often sufficiently water soluble to produce solutions for all foreseeable needs. The carrier material may contain small amounts of additives, such as substances that improve solubility, isotonicity and chemical stability, such as antioxidants, buffering agents and preservatives.

For rectal administration, the compositions of the present invention are formulated in a unit dosage form such as suppositories or capsules. The compositions may be prepared by mixing the compound of the present invention with a suitable non-irritating excipient or excipients which are solid at room temperature but which are liquid at the rectal temperature, for example those which melt at the rectal temperature to release the active compound. . Commonly used excipients include cocoa butter, beeswax and polyethylene glycols and other fatty emulsions or suspensions.

In addition, the compounds of the present invention may be used

9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9

The invention may be administered topically, particularly when there are conditions in the treatment where the treatment can be performed on surfaces or organs readily accessible by topical application, for example in neurological disorders of the eye, skin or lower intestinal tract.

For topical (topical) application of the eye or for ophthalmic use, the compounds of the present invention are formulated as micronized suspensions in isotonic, pH adjusted, sterile saline, or preferably isotonic, pH adjusted, sterile saline with or without addition preservatives such as benzylalkonium chloride. Alternatively, the compounds of the present invention may be formulated in an ointment such as petrolatum.

For topical application to the skin, the compounds of the present invention may be formulated into suitable ointments containing the compounds suspended or dissolved in, for example, mixtures containing one or more of: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene compound, polyoxypropylene compound, emulsifying wax and water. Alternatively, the compounds of the present invention may be formulated into suitable lotions or creams containing the active compound suspended or dissolved, for example, in a mixture comprising one or more of the following: mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

Topical application to the lower intestinal tract is • ··

44 444 44 444 · 3 ·

4444 4444 4444

44 44 44 44 44 can be carried out using rectal suppository formulations (see above) or in the form of suitable enema formulations.

Formulations suitable for nasal or buccal administration (such as self-propulsion powder formulations) may be formulated to contain from about 0.1% to about 5% by weight of the active agent, e.g. of the active ingredient was about 1% by weight based on the total weight. In addition, some formulations may be formulated as a sublingual dragee or lozenge.

The formulations of the present invention may be prepared in unit dosage form using any of the methods well known in the art of pharmacy for their preparation. However, all of these methods include the step of bringing the active ingredient into association with the carrier material which constitutes one or more excipients. In general, these formulations are prepared in such a way that the active ingredient is intimately combined with the liquid carrier or the finely divided solid carrier, or both, in a homogeneous manner and then, if desired, formed into the desired formulation.

Preferably, the composition is administered in the form of a capsule or tablet containing a single dose or divided dose of the inhibitor of the present invention, or a sterile solution, suspension or emulsion for parenteral administration in single or divided dose form.

According to another preferred embodiment, the compounds may be

0 0 0 0 0

0000 0 00 0

000 · 0 «

0 0 0 0 0 ·

According to the present invention, the PARP inhibitors are administered in a lyophilized form. In this case, 1 to 100 milligrams of PARP inhibitor can be lyophilized in individual tubes together with a carrier and a buffer such as mannitol or sodium phosphate. The compound may be reconstituted with bacteriostatic water in these tubes prior to administration.

Preferably, the carrier material is a solid biodegradable polymer or a blend of biodegradable polymers with suitable time release characteristics and suitable release kinetics. The composition of the present invention can then be shaped into a suitable implant containing an effective concentration of the compound of the present invention released over long periods of time without frequent re-dosing. The composition of the present invention may be incorporated into a suitable biodegradable polymer or polymer blend by any suitable method known to those skilled in the art, and may be in the form of a homogeneous matrix with the biodegradable polymer or may be a biodegradable polymer. the encapsulated form in any suitable manner in the polymer, or the compound may be sealed into a suitable solid implant.

In one embodiment of the invention, a biodegradable polymer or polymer blend is used to form a soft depot bearing containing the pharmaceutical composition of the present invention, which can be applied as a flowable fluid by injection, for example, but remains viscous enough to maintain

A pharmaceutical composition in a localized area around the injection site. The disintegration time of the depot deposited in this way can vary from several days to several years, depending on the polymer selected and its molecular weight. The use of the polymer composition in injectable form can even eliminate the need for incision. In any case, the flexible or flowable applied depot bearing adapts to the shape of the site that occupies the body with minimal trauma to surrounding tissues. The pharmaceutical composition of the present invention is used in an amount that is therapeutically effective and may depend upon the desired release profile, the concentration of the pharmaceutical composition necessary for a sensitizing effect, and the length of time the pharmaceutical composition is to be therapeutically released.

PARP inhibitors are used in the composition in an amount that is therapeutically effective. While the effective amount of PARP inhibitor will depend upon the particular PARP inhibitor employed and the dosage form employed, it will generally be appreciated that the amount of PARP inhibitor that can be readily incorporated into the liquid or solid carrier material of the delivery system is in the range from about 0.1 wt% to about 75 wt%, preferably from about 1 wt% to about 65 wt%, and more preferably from about 1 wt% to about 50 wt%,

Methods for influencing neuronal activity

In the methods of the present invention, an effective therapeutic amount of the compounds is administered. ** ftft ftft ftft ftft ft ft ft ft ft ft ft ft ft ft ft and the compositions described above to animals to affect neuronal activity, preferably a type of activity that is not mediated by NMDA neurotoxicity. This neuronal activity may include stimulating damaged neurons, promoting neuronal regeneration, preventing neurodegeneration, and treating a neurological disorder. Accordingly, the present invention further relates to a method of affecting neuronal activity in an animal comprising administering to the animal an effective amount of a compound of Formula I of the present invention. In addition, the compounds of the invention inhibit PARP and are therefore believed to be useful in the treatment of nerve tissue damage, particularly damage resulting from cerebral ischemia and reperfusion injury or neurodegenerative diseases in mammals.

The term nerve tissue refers to various components that make up the nervous system, including, but not limited to, neurons, neural support cells, glia, Schwann cells, the vascular supply contained in these structures, and the vascular supply that provides these structures. , the central nervous system, brain, brainstem, spinal cord, connection of the central nervous system to the peripheral nervous system, the peripheral nervous system, and related structures.

The term nerve tissue damage resulting from ischemia and reperfusion injury and neurodegenerative diseases includes neurotoxicity as seen in stroke and global and focal ischemia.

The term neurodegenerative diseases includes

00 • 4 4 • 0 00

44

00 ·· ··

0 0 0 0 0 0

4,000 · 0 · *

40,004 40 0

00 0 0 41 0

40 04 0 ·

Alzheimer's disease, Parkinson's disease and Huntington's disease.

The term nerve damage refers to any damage to nerve tissue and any inability or death resulting from such damage. The cause of the nerve injury may be metabolic, toxic, neurotoxic, iatrogenic, thermal or chemical, and without limiting the present invention, ischemia, hypoxia, cerebrovascular accident, trauma, surgery, pressure, mass, bleeding may be included , radiation, angiospasm, neurodegenerative disease, infection, Parkinson's disease, amyotrophic lateral sclerosis (ALS), epilepsy, myelinating / demyelinating process, cognitive disorders and glutamate abnormalities and its secondary effects.

The term neuroprotective refers to the effect of reducing, arresting or alleviating nerve damage and protecting, reviving or reviving nerve tissue that has suffered from nerve damage.

The term prevention of neurodegeneration includes the ability to prevent neurodegeneration in patients who have been diagnosed with a neurodegenerative disease or who are at risk of developing a neurodegenerative disease. The term also includes preventing further neurodegeneration in patients who already have a neurodegenerative disease or have symptoms of a neurodegenerative disease.

Examples of neurological disorders that are treatable by the methods of applying the present invention and without limiting the scope of the invention include trigemine neuralgia, glosopharyngeal neuralgia,

- 84 muscular dystrophy, progressive muscular «· *’

I 9 ·· ► 9 I k »9 I

9C> · 999 »· 1 i · and <1

9 9 9 9 9 9

9 9

99

Bell's stump, myasthenia gravis, amyotrophic lateral sclerosis, atrophy, hereditary progressive bulbar muscle atrophy, hernia, rupture or prolapse of the intervertebral disc, cervical spondylosis, diseases associated with neural plexuses, oppression syndrome of the thoracic aperture such as peripheral neuropathy, peripheral neuropathies dapson, ticks, porphyria or Guillain-Barré syndrome, Alzheimer's disease, Huntington's disease and Parkinson's disease.

The method of the present invention is particularly useful for treating a neurological disorder selected from the group consisting of peripheral neuropathy caused by somatic injury or disease state, traumatic brain injury, somatic spinal cord injury, cerebrovascular accident associated with brain injury, demyelinating disease and neurological disorders related to neurodegeneration. Examples of demyelinating diseases include multiple sclerosis. Examples of neurological disorders related to neurodegeneration include Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS).

The term treatment refers to:

(i) preventing a disease, disorder or condition before it occurs in an animal that may be predisposed to the disease, disorder or condition but not yet diagnosed; (ii) inhibiting the disease, disorder or condition, i. or (iii) relieving the disease, disorder or condition, i.e., causing regression of the disease, disorder, and / or condition.

*

► 0 0 0 ► 00 «0

000

Treatment of other disorders related to PARP

The compounds, compositions and methods of the present invention are particularly useful for treating or preventing tissue damage that results from cell death or damage caused by necrosis or apoptosis.

The compounds, compositions and methods of the invention may also be used to treat cardiovascular diseases in an animal by administering to the animal an effective amount of a compound of the present invention.

The term cardiovascular disease, as used herein, refers to those diseases that may be caused by either ischemia or by reperfusion of the heart. Examples of such diseases include, but are not limited to, ischemic heart disease, angina pectoris, myocardial infarction, cardiac vascular damage caused by cardiac arrest, cardiac bypass injury, cardiogenic shock, and related other disease states that are known to those skilled in the art, or which include dysfunction or tissue damage to the heart or vascular supply, in particular, but not limited to, tissue damage in relation to activation of PARP.

For example, according to the invention, it is believed that the methods of the invention are useful for treating cardiac tissue damage, particularly injury that occurs in animals due to cardiac ischemia or due to reperfusion injury. The methods of the invention are particularly useful for the treatment of cardiovascular diseases selected from the group consisting of ischemic heart diseases such as atherosclerosis, angina. 0 · 0β0 ·· ·· 0 0 00 pectoris, myocardial infarction, myocardial ischemia and cardiac arrest, cardiac bypass and cardiogenic shock. The methods of the invention are particularly useful in the treatment of acute forms of the aforementioned cardiovascular diseases.

The methods of the invention can further be used to treat tissue damage resulting from cell damage or cell death caused by necrosis or apoptosis, nerve tissue damage resulting from ischemia and reperfusion injury, neurological disorders and neurodegenerative diseases, prevention or treatment of cerebral vascular events, for the treatment or prevention of cardiovascular diseases, for the treatment of other conditions and / or disorders such as age-related macular degeneration, AIDS and other immune diseases senescence, arthritis, atherosclerosis, cachexia, cancer, skeletal muscle degenerative diseases including replication senescence diabetes, head trauma, immune senescence, inflammatory bowel disease (such as colitis and Crohn's disease), muscular dystrophy, osteoarthritis, osteoporosis, chronic and / or acute pain (such as neuropathic pain), renal failure, retinal ischemia, s eptic shock (such as endotoxic shock) and skin aging, to prolong the life span and cell proliferative capacity, to alter the gene expression of senescent cells, or to induce radiation sensitivity (radiosensitivity) in hypoxic tumor cells.

In addition, the method of the invention can be used to treat cancer and to induce radiation sensitivity in tumor cells. The term cancer must be interpreted in its broad meaning. The compounds of the present invention may be anti-cancer agents, and the term also includes anti-cell growth agents.

4 4 • 4 4 4 <4 «· tumors and antineoplasic agents. The methods of the invention are useful, for example, for the treatment of cancer and inducing radiation sensitivity in cancer cells in carcinomas such as ACTH-producing tumors, acute lymphocytic leukemia, acute non-lymphocytic leukemia, adrenal cortex cancer, bladder cancer, brain cancer, breast cancer, uterine cancer suppository, chronic lymphocytic leukemia, chronic myelocyte leukemia, colorectal cancer, skin T cell lymphoma, endometrial cancer, esophageal cancer, Ewing's sarcoma, gallbladder cancer, hairy leukemia, neck and head cancers, Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer, , lung carcinoma (small cell and / or non-small cell), malignant peritoneal effusion, malignant pleural effusion, melanoma, mesothelioma, multiple myeloma, neuroblastoma, non-Hodgkin's lymphoma, osteosarcoma, ovarian cancer, ovarian prostate cancer, pancreatic cancer, penile cancer, retinoblastoma, skin cancer, soft tissue sarcoma, squamous cell carcinomas, gastric cancer, testicular cancer, thyroid cancer, trophoblast neoplasms, uterine cancer, vaginal cancer, vulva cancer, and Vilms tumor.

The term "radiosensitizer" as used herein, i.e., radiation sensitivity enhancer, is defined as a molecule, preferably a low molecular weight molecule, administered to an animal in a therapeutically effective amount to increase the sensitivity of the cells to achieve radiosensitivity to electromagnetic radiation and / or to promote the treatment of diseases that are treatable by electromagnetic radiation. Diseases that are treatable by electromagnetic radiation include neoplasms, benign and malignant tumors, and cancer cells.

other diseases that the present invention

Electromagnetic radiation treatments are not included in this list, but are also contemplated. Within the scope of the terms electromagnetic radiation and radiation used in the description of the present invention, it is possible to include, but is not limited to, radiation having a wavelength of 10 ^- 10 ° to 10 ° m. -1 * 3 electromagnetic radiation: gamma-rays (10 to 10 meters), X-rays (ΙΟ ” ¹¹ to 10” ^ meters), ultraviolet light (10 nm 400 nm), visible light (400 nm to 700 nm), infrared radiation (700 nm to 1.0 mm) and microwave radiation (1 mm to 30 cm).

Radiosensitizers are known to increase the sensitivity of cancer cells to toxic effects of electromagnetic radiation. Several mechanisms have been suggested in the literature for the mode of action of these radiosensitizers, including:

radiosensitizers for hypoxic cells (e.g.

2-nitroimidazole compounds and benzotriazine dioxide compounds) promote the reoxygenation of hypoxic tissue and / or catalyze the formation of destructive oxygen radicals, radiosensitizers for nonhypoxic cells (e.g., halogenated pyrymidines) may be DNA analogues and preferentially incorporate into cancer cell DNA, thereby promoting molecular breaks Radiation-induced DNA and / or prevent normal mechanisms for DNA repair, hypotheses of various other potential mechanisms of action of radiosensitizers in the treatment of diseases have been suggested.

According to many cancer treatment methods, radiosensitators activated by X-ray electromagnetic radiation are currently used. As examples of X-ray activated radiosensitizers, with • · • 0 · *

0

However, this is not limited to the following: metronidazole, mizonidazole, desmethylmizonidazole, pimonidazole, etanidazole, nimorazole, mitomycin C, RSU 1069, SR 4233, E09, RB 6145, nicotinamide, 5-bromodeoxyuridine (BUdR) , 5-iododeoxyuridine (IUdR), bromodeoxycytidine, fluorodeoxyuridine (FUdR), hydroxyurea, cisplatin and therapeutically active analogs and derivatives thereof.

Photodynamic therapy (PDT) of cancer uses visible light as a radiation activator of the sensitizing agent. Examples of photodynamic radiosensitizers include, but are not limited to: hematoporphyrin derivatives, Photofrin, benzporphyrin derivatives, NPe6, stannous etioporphyrin SnET2, phoboborbide, bacteriochlorophyll a, naphthalocyanines, phthalocyanines, and phthalocyanine, phthalocyanine therapeutically active analogs and derivatives.

Radiosensitizers may be administered in conjunction with a therapeutically effective amount of one or more other compounds, including compounds that promote the incorporation of radiosensitizers into target cells, compounds that control the delivery of drugs, nutrients and / or oxygen to the target cells, chemotherapeutic agents that act on the tumor. radiation and / or without such radiation, but the examples are not limited thereto, or other therapeutically active compounds for the treatment of cancer or other diseases. Examples of other therapeutic agents that may be used in conjunction with radiosensitizers include, but are not limited to: 5-fluorouracil, leucovorin,

5'-amino-5'-deoxythymidine, oxygen, carbon, red blood cell transfusions, perfluorocarbons (e.g. Fluosol-DA), 2,3-DPG, BV12C, calcium channel blockers, pentoxyphylin, anti-vascular regrowth, hydralazine, and L-BSO. Examples of chemotherapeutic agents that may be used in conjunction with radiosensitizers include, but are not limited to: camptothecin, carboplatin, cisplatin, daunorubicin, docetaxel, doxorubicin, interferon (alpha, beta, gamma), interleukin 2, irinotecan, paclitaxel, topotecan and therapeutically active analogs and derivatives thereof.

The compounds of the present invention may also be used to induce radiation sensitivity in tumor cells.

The term treatment as used herein means:

(i) preventing a disease, disorder or condition before it occurs in an animal that may be predisposed to, but not yet diagnosed with the disease, disorder or condition; (ii) inhibiting the disease, disorder or condition, i.e. stopping its development; or (iii) relieving the disease, disorder or condition, i.e., causing regression of the disease, disorder and / or condition.

Administration

When applying the methods of the present invention, the compounds of the invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally,

Sublingually, vaginally or via an implanted reservoir in dosage formulations containing conventional non-toxic pharmaceutically acceptable carriers or any of the following: another commonly used substance, adjuvant or vehicle. The term parenteral as used herein includes subcutaneous, intravenous, intramuscular, bone, intraperitoneal, intrathecal, intraventricular, intrasternal and intracranial injection or infusion techniques, as well as a subdural pump. Invasive technique is preferred in this case, particularly direct administration into damaged neuronal tissue.

In order for the compounds of the present invention to be therapeutically effective in targeting the central nervous system, the compounds used in the methods of the present invention should readily cross the blood-brain barrier when peripherally administered. However, compounds that cannot penetrate the blood-brain barrier may nevertheless be effectively administered by the intraventricular route.

The compounds used in the methods of the present invention may be administered in a single dose, multiple single doses, or as a continuous infusion. Since the compounds of the present invention are small, easily diffusing and relatively stable, they are suitable for continuous infusion. Pumps, in particular a subcutaneous pump or subdural pump, are preferred for continuous infusion.

For therapeutic use, the amount of a compound of Formula I of the invention necessary to achieve a therapeutic effect will vary with the particular compound, the route of administration, the mammal being treated, and the particular disorder or disease being treated. It is understood that a normally experienced doctor or veterinarian * · ·· • · · «

J * ♦ · · · · · · · * ·· ·· ·· 99> Fe · ♦ »► 9 9 9 9 · ¹ 9 9 9 ·· Fefe readily determine and prescribe the effective amount of compound to the desired prophylaxis or therapy. In this procedure, the physician or veterinarian may use an intravenous bolus followed by intravenous infusion and repeated administration, orally or parenterally, as it deems appropriate. While it is possible for the compound of the formula I to be administered alone, it is preferable to provide it in the form of a pharmaceutical composition or composition.

Dosages of the compounds preferably include pharmaceutical dosage units containing an effective amount of the active compound. By an effective amount is meant an amount sufficient to inhibit PARP and obtain a beneficial effect therefrom through administration of one or more pharmaceutical dosage units. The dose is preferably sufficient to prevent or reduce the effect of stroke or other neurodegenerative diseases.

An example of a daily vertebrate dosage unit is about 0.001 milligrams / kilogram to about 50 milligrams / kg. Dosage levels in the range of about 0.1 milligram to about 10,000 milligrams of the active ingredient of the compound are preferably useful in the treatment of the aforementioned conditions, with even more preferred levels in the range of about 0.1 milligrams to about 1,000 milligrams. the dosage of a compound of the invention of formula I for mammals suffering from, or likely to be suffering from, any of the conditions described herein ranges from about 0.1 milligram to about 100 milligrams of compound per kilogram of body weight, and most preferably from about 1 milligram to about 10 milligrams. kg of mammal body weight.

Specific dose level for each specific • 0 ·· ♦ · 0 0 * · 00 ¹ 0 0 ¹ 0 0 ·· 00 • · 0 0 • 0 0 0

The patient depends on a variety of factors including the activity of the specific compound used, age, body weight, overall health, sex, diet, time of administration, elimination rate, combination of the compound with other drugs, the severity of the particular disease being treated, the form of the medicament, and the mode of administration. Usually, the in vitro results of the dose-dependent treatment provide useful guidance as to the appropriate doses to be administered to patients. Studies in animal models also aid in the determination of these doses.

Factors determining the correct dose level are well known in the art.

In procedures for treating nerve damage (particularly acute ischemic stroke and global ischemia due to drowning or head trauma), the compounds of the invention may be co-administered with one or more other therapeutic agents, preferably agents that can reduce the risk of stroke (such as aspirin) and more preferably formulations that can reduce the risk of a second ischemic event (such as ticlopidine).

The compounds and compositions of the present invention may be coadministered with one or more therapeutic agents either (i) in the form of a single formulation or (ii) separately as individual formulations designed to achieve optimal release rates of their respective active agents.

Each composition may contain from about 0.01% to about 99.99% by weight of the compound of the present invention, preferably from about 3.5% to about 60% by weight of the compound of the present invention, as well as from about 3.5% by weight to the compound of the present invention. one or more • 0 0

0 0

0 0

0 0 0 0 0 0 0 0

pharmaceutical excipients such as wetting agents, emulsifying agents, and pH buffering agents (or buffers). Where the compounds used in the methods of the present invention are administered in combination with one or more therapeutic agents, then the specific dosage amount of these agents will depend upon the factors set forth above for the compounds, compositions and methods of the invention in general.

Table VII shows the known average doses of selected chemotherapeutic agents that can be administered in combination with the compounds of the present invention to treat diseases such as various cancers.

0 0 0 0 0 0 0 0 0 0 0 0 0

0 0

0 0

0 0

00

TABLE VII

Chemotherapeutic agent

Average dose

Asparaginase 10,000 units Bleomycin Sulphate 15 units Carboplatin 50 - 450 milligrams Carmustine 100 milligrams Cisplatin 10 - 50 milligrams Cladribine 10 milligrams Cyc1ophos pham and de 100 milligrams to 2 grams (lyophilized) Cyclophosphamide 100 milligrams to 2 grams (non-lyophilized) Cytarabine 100 milligrams to 2 grams (lyophilized powder) Dacarbažině 100 to 200 milligrams Dactinomycin 0.5 migram Daunorubicin 20 milligrams Diethylsilbestrol 250 milligrams Doxorubicin 10 to 150 milligrams Etidronate 300 milligrams Etoposide 100 milligrams Floxuridine 500 milligrams Fludarabine Phosphate 50 milligrams Fluorouracil 50 milligrams to 5 grams Goserelin 3.6 milligrams Granisetron Hydrochloride 1 milligram Idarubicin 5 to 10 milligrams lfosfamide 1 to 3 grams Leucovorin Calcium 50 to 350 milligrams

• · 4 ·· 44 • 4 • · 4 »0 0

0 0

0 0 0 0 0

TABLE VII (continued)

Chemotherapeutic agent Average dose Leuprolide 3.75 - 7.5 milligrams Mechlorethamine 10 milligrams Medroxyprogesterone 1 gram Melphalan 50 grams Methotrexate 20 milligrams to 1 gram Mitomycin 5 to 40 milligrams Mitoxantrone 20 to 30 milligrams Ondansetron Hydrochloride 40 milligrams Paclitaxel 30 milligrams Pamidronate Disodium 30 to 90 milligrams Pegaspargase 750 units Plicamycin 2500 micrograms Streptozocin 1 gram Thiotepa 15 milligrams Teniposide 50 milligrams Vinblastine 10 milligrams Vincristine 1 to 5 milligrams Aldesleukin 22 million units Epoetin Alfa 2000 to 10,000 units Filgrastim 300 to 480 micrograms Immune Globulin 500 milligrams to 10 grams Interferon Alpha-2a 3 to 36 million units Interferon Alpha-2b 3 to 50 million units Levamisole 50 milligrams Octreotide 1000 to 5000 micrograms Sargramostim 250 to 500 micrograms

• · 9

9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 999 9 999 9 9

Any mode of administration that controls the timing and sequence of compound administration can be used for the methods of the present invention and can be repeated as necessary to effect treatment. Such regimen may include preventative treatment and / or co-administration with other therapeutic agents.

In order to maximize the protective effect on nerve tissue from nerve injury, the compounds of the present invention should be administered to the affected cells as soon as possible. In situations where nerve damage can be predicted, the compounds should be administered prior to the expected nerve damage. Such situations of increased likelihood of neural damage include surgery (carotid endarterectomy, cardiac, vascular, aortic, orthopedic surgery), endovascular procedures such as arterial catheterization (carotid catheterization, vertebral arteries, aortic, cardiac, renal vessels, spinal vessels, Adamkiewicz) ), injection of embolusable products, a ring or balloon to stop bleeding, interruption of the vascular supply in the treatment of brain lesions, and predisposing disease states such as escalating transient cerebrovascular accidents, embolism and successive strokes.

In cases where preventive treatment for stroke or ischemia is impossible or impracticable, it is important to get the compounds of the invention to the affected cells as soon as possible during or after the event.

In the time period between stroke, diagnostic and therapeutic procedures should be minimized to protect the cells from further damage and death.

· · · · · · · · · · · · · · · · · · · · · · · · · · ·

A particularly preferred mode of administration for a patient diagnosed with an acute stroke is via implantation of a subdural pump to administer the compounds (s) of the invention directly to the infarct area of the brain. Even if the patient is in a coma, they are expected to recover faster than if they did not receive the compound of the invention. In addition, residual neurological symptoms are expected to be reduced and the recurrence of stroke is reduced.

Depending on the patient's current symptoms and response to compound administration, the patient may receive the same or different compound, parenterally, by injection or intravenous administration, orally, capsule or tablet, by implanting a delivery system that is biocompatible and biodegradable a matrix comprising a compound of the formula I according to the invention or by direct administration to the infarct area by insertion of a subdural pump or central catheter. Treatment is expected to lessen the disorder either partially or completely, and there will be no or fewer other events. The patient is also expected to suffer from minor residual symptoms.

Examples of such disorders include, for example, peripheral neuropathy due to somatic injury, peripheral neuropathy due to a disease state, Guillain-Barre syndrome, head trauma, somatic spinal cord injury, stroke associated with hypoxia and brain damage, focal cerebral ischemia, global cerebral ischemia, global cerebral ischemia cerebral reperfusion injury, demyelinating disease, multiple sclerosis, neurodegeneration-related neurological disorder, Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic

Lateral sclerosis (ALS), cardiovascular diseases such as acute coronary artery disease, acute cardiogenic shock, acute myocardial infarction, acute ischemia · · 9 · 9 · 9 · 9 · 9 · 9 myocardium, complete cardiac and respiratory arrest, septic shock, diabetes, arthritis, inflammatory bowel disease such as colitis or Crohn's disease and cancer.

In cases where a patient is diagnosed with an acute disorder before the compound of formula I is available, the patient's condition may deteriorate due to the disorder and by the time the compound of formula I is available, the disorder may become chronic condition. Even if the patient received the compound after the condition has become chronic, further improvement and stabilization of the condition due to administration of the compound is expected.

4 4 4 4

4 •

4 4 · 4 4

100 ALIGN!

DETAILED DESCRIPTION OF THE INVENTION

The invention will now be described in more detail with reference to the following non-limiting examples, which are illustrative only and illustrate certain preferred embodiments of the invention. All molecular weights of polymers are meant as average molecular weights. All percentages are by weight based on the prepared final release system or composition, unless explicitly stated otherwise, and the total proportions are 100% by weight.

Example 1

Approximate IC 50 values for selected compounds.

ICP values for PARP inhibition were determined for some compounds by the PARP assay using purified recombinant human PARP obtained from Trivigen (Gaithersburg, MD) as follows: the test PARP enzyme was placed on ice in a volume of 100 microliters containing 10 mM Tris-HCl ( pH 8.0), 1 mM MgCl ₂ , 28 mM KCl, 28 mM NaCl, 0.1 mg / ml herring sperm DNA (activated as 1 mg / ml stock solution for 10 minutes in 0.15% sodium peroxide solution) 3.0 micromolar [3 H] nicotinamide adenine dinucleotide (470 mci / mmol), 7 micrograms / ml PARP enzyme, and various concentrations of test compounds. This reaction was initiated by incubating the mixture at 25 ° C. After 15 minutes incubation, this reaction was terminated by the addition of 500 microliters of ice cold 20% trichloroacetic acid (w / v). The resulting precipitate was transferred to a glass fiber filter (Packard Unifilter-GF / B) and washed three times with ethanol. After this filter was dried, it was 4 4 4 4 4 4

Radioactivity determined by scintillation counting. The compound of the present invention has been found to exhibit effective enzymatic activity in the range of tenths of μΜ to 20 M with respect to an IC ₅ q value of this assay. IC 50 values for the following compounds are shown in Table VIII below.

TABLE VIII

compound The approximate IC value is ₅ g 0 1 1.6 µM 1 <^ NH IN NO 2 5 1.3 µM I 'I 'NH II 1 1 χ 10 UM Π « COOH

•

103 · * ·

TABLE VIII (continued)

| compound ^! Approximate IC50 value 3.4 µM what 50 µM οφ COOC} -b 0.3 UM ργ-Νκ kAA 4 μΜ p ^ H 100 μΜ

0 «»

- 103 • ·· 0 »0

TABLE VIII (continued)

R η

- 104 · «104 104 104 104 104 104 104 104 104 104 104 104 104 104 104 104 104 104

• 0

00

- 105 TABLE VIII (continued)

- 106 TABLE VIII (continued)

compound Approximate IC ₅₀ ' \\ 'Ν— N 0 ₂ N 0.30 / Χ ”/ / ° H ₃ C VJ Μ —N 0 ₂ N 0.6S H ₃ C> -7 NN H ₂ N 0.22 Ν— N 4.0 , χτο3ϊ \ ζ χ — 0 Ν — Ν 1.3 0 0.76

- 107 £ '· · · · · · ·

• · β

TABLE VIII (continued)

compound = - 'n— ^XJ —— = - ------- if Approximate IC _5Q value 0 0.31 AND AND AND 1 ch ₃

108

Example 2

Test of neuroprotective effect on focal cerebral ischemia in rats

Focal cerebral ischemia experiments were performed using male Vistar rats weighing 250-300 grams and anesthetized

4% halothane. Anesthesia was maintained with 1.0-1.5% halothane until the end of surgery. The animals were housed in a warm environment to prevent a decrease in body temperature during surgery. An incision was made in the anterior cervical line. The true common carotid (CCA) was uncovered and separated from the vagus nerve. A silk stitch was established around the CCA and ligated near the heart. The outer carotid artery (ECA) was then exposed and ligated with a silk stitch. A small puncture was made into the CCA and a small catheter (PE 10, Ulrich & Co., St-Gallen, Switzerland) was gently pushed forward into the lumen of the internal carotid (ICA). The pterygopalatin artery has not been closed. The catheter was fixed in place with a silk stitch.

4-0 nylon fiber (Braun Medical, Crissier, Switzerland) was then inserted into the lumen of the catheter and the catheter was advanced until the tip blocked the a. Anterior cerebri. The length of the catheter inserted into the ICA was approximately 19 millimeters from the onset of ECA. The fiber was held in this position by catheter occlusion due to heat. One centimeter of the catheter and the nylon fiber was allowed to protrude so that the fiber could be pulled out and allowed reperfusion. The cutaneous incision was then closed.

During recovery from anesthesia, the animals were kept warm. Two hours later the animals were again

- 109 -

anesthesia was given, the clamps were removed and the wound reopened. The catheter was incised and the fiber was withdrawn, after which the catheter was closed again by heat and the wound was closed with clips. Animals were allowed to survive for 24 hours with free access to food and water. The rats were killed by CO 2 and decapitated.

Brains were immediately removed, frozen on dry ice, and stored at -80 ° C. Brains were then cut in 0.02 mm thick sections on a cryostat at -19 ° C and one section was taken from every 20 sections. Sections were stained with cresyl violet according to the Nissl method. Each stained section was examined by light microscopy and the infarct area was determined by the occurrence of cells with morphological changes.

Various doses of compounds of the invention were tested in this model. The compounds were administered either in a single or a series of multiple doses, intravenously or intraperitoneally, as a single dose or a series of multiple doses, at different times before or after the onset of ischemia. In this test, the compounds of the present invention have been found to protect against ischemia in the range of 20 to 80%.

Example 3

Test of neuroprotective effect on focal cerebral ischemia in rats

Female Sprague-Dawley rats, each weighing 300-350 grams, were anesthetized with intraperitoneal ketamine at a dose of 150 mg / kg. Rats were endotracheally intubated and ventilated with oxygen-enriched room air using a Harvard rodent fan. Polyethylene catheters embedded in carotid • 0 • 0 · 0 • 00

- 110

00 000 00 0 0 0 0 0 V • 00 0 0 00 0 00 00 0 0 0 0 · 0 * 0 0 · 0 * · and femoral veins were used to monitor arterial blood pressure and to administer fluids. Arterial pCC> 2 was maintained between 35-45 mm Hg by adjusting respiratory rate.

The rat chest was opened with a midline sternotomy, pericardium was incised, and the hearts were surrounded by a latex membrane tent. Baseline hemodynamic data was collected after at least 15 minutes of stabilization after surgery. The LAD (left anterior descending) coronary artery was ligated for 40 minutes followed by 120 minutes of reperfusion. After 120 minutes of reperfusion, the LAD artery was resealed and 0.1 ml of a monastral dye bolus was injected into the left atrium to determine the area at risk of ischemia.

The hearts were then stopped with potassium chloride and cut into five 2 to 3 mm thick cross sections. Each section was weighed and incubated in a 1% solution of triphenyltetrazolium chloride to visualize the myocardial infarction located in the risk area. Infarct size was calculated from the sum of the values for each left ventricular section and expressed further as the proportion of the left ventricular risk area.

Various doses of compounds of the invention were tested in this model. The compounds were administered either intravenously or intraperitoneally, as a single dose or as a series of multiple doses, at different times before or after the onset of ischemia. In this test, the compounds of the invention were found to act as protective agents for ischemia / reperfusion injury in the range of 10 to 40%.

Example 4

Test of neuroprotective effect on focal cerebral

- 111 9 9 <9 9 9

9 9 9 * 9.9 · »9 9

Ischemia in rats

Focal cerebral ischemia was created by cautery the right distal MCA (a. Cerebri media) with a temporary bilateral occlusion of the common carotid artery in male Long-Evans rats for 90 minutes. All animal procedures have been approved by the University Institutional Animal Care and the Use Committee of the University of Pennsylvania.

A total of 42 rats (230-340 grams) obtained from Charles River were used in this study. Before surgery, the animals were fasted overnight with free access to water.

Two hours prior to MCA occlusion, different amounts were dissolved (control, n = 14; 5 mg / kg, n = 7; 10 mg / kg, n = 7; 20 mg / kg, n = 7; and 40 mg / kg, n). = 7) compounds

3,4-dihydro-5- [4- (1-piperidinyl) -butoxy] -1 (2H) -isoquinoline (DPQ) in dimethylsulfoxide (DMSO) using a sonicator. Fourteen rats were injected intraperitoneally with a volume of 1.28 ml / kg of the resulting solution.

Rats were then anesthetized with halothane (4% initially and 0.8% and 1.2% during surgery) in a mixture of 70% nitrous oxide and 30% oxygen. Body temperature was monitored by rectal probe and maintained at 37.5 + 0.5 ° C by a heated blanket controlled by a homeothermal control unit (Harvard Apparatus Limited, Kent, UK). A catheter (PE-50) was placed in the tail artery and the arterial pressure was continuously monitored and recorded on a grass polygraph (Model 7D, Grass Instruments, Quincy, Massachsetts). Blood gas analysis samples (arterial pH, PaC> 2 and PaCC ^) were also taken from the tail artery catheter and measured on a blood gas analyzer (ABL).

0 0 0 0

- 112 • 0 · 0 0

0 0 0 * 0

30, Radiometer, Copenhagen, Denmark). Arterial blood samples were collected 30 minutes after MCA occlusion.

The head of the animal was placed in a stereotactic holder and a true parietal incision was made between the right outer eye corner and the outer ear canal. Using a permanently-cooled dental drill, a 3 millimeter drill hole was made above the cortex supplied with the right MCA, 4 millimeters lateral to the sagittal seam and 5 millimeters caudally to the coronal seam. Dust mater and a thin inner bone layer were retained, taking care to position the probe above the tissue area without large blood vessels. The flow probe (tip diameter 1 millimeter, fiber separation 0.25 millimeter) was lowered to the bottom of the cranial bore using a micromanipulator. The probe was held in a stationary position by the probe holder attached to the skull with dental cement. Microvascular blood flow in the right paritary cortex was continuously monitored by a laser Doppler flow meter (FloLab,

Moor, Devon, UK, and Periflux 4001, Perimed, Stockholm, Sweden).

Focal cerebral ischemia was created by cauterization of the distal part of the right MCA with a temporary bilateral common carotid occlusion (CCA) according to a procedure known in the literature. Chen et al. (Model of Focal Ischemia Stroke in the Rat: Stroke, Reproductive Extensive Cortical Infarction, Stroke,

17, 738-43, 1986) and / or Liu et al. (Polyethylene Glycol-Conjugated Superoxide Dismutase and Catalase Reduce Ischemia Brain Injury, Am. J. Physiol., 256, H589-93,

1989), which are incorporated herein by reference.

More specifically, CCA and around CCA have been isolated bilaterally

- 112 » ^W 0 | ^W 4 0 '♦ * ♦ 44 0 44 0 4 0 4 * 4 · 4 0 0 0 9 9 0 4

0 0 44 · 4 · «· · loops made of polyethylene (PE-10) catheter were carefully established for later distant occlusion. The incision that was previously made to locate the laser Doppler probe was expanded to allow observation of the rostral end of the zygomatic arc at the junction point using a dental drill, and the denture overlapping the MCA was cut through. The MCA was lifted distally from its crossing with a v. Inferior cerebri fine stainless steel hook that was attached to a micromanipulator and after bilateral occlusion of the CCA, the MCA was cauterized by electrocoagulation equipment. The drilled hole was covered with a small piece of Gelform, and the wound was sutured to keep the brain temperature within or near the normal range.

After 90 minutes of occlusion, the loops on the carotid arteries were loosened, the tail artery catheter was removed, and all wounds were sutured. Gentamycin sulfate (10 mg / ml) was topically applied to the wounds to prevent infection. Administration of the anesthetic was discontinued and the animal was returned to the cage after waking up. Access to water and food was provided ad libitum.

Two hours after MCA occlusion, the animals were given the same dose of PARP inhibitor as given prior to treatment. 24 hours after MCA occlusion, rats were sacrificed by intraperitoneal injection of sodium pentobarbital (150 mg / kg). The brain was carefully removed from the skull and cooled for 5 minutes in an ice-cold artificial CSF. The cooled brain was then dissected in a coronal plane at 2 mm intervals using a rodent brain matrix (RBM-4000C, ASI Instruments, Varren, Michigan). Brain sections were incubated in phosphate buffered saline containing 2%

2,3,5-triphenyltetrazolium chloride (TTC) at 37 ° C for 10 minutes. The back surface of the stained sections was * 0 · 0

0 00

0 0 0

0 0 0 · <

· 0

0 0 0 0 • <0 0 «0

- 114 were taken and the photographs were used to determine the damaged area of each cross-section plane using a computerized image analyzer (NIH Image 1.59). To prevent edema artifacts, the damaged area was calculated by subtracting the normal tissue area in the hemisphere ipsilaterally to a stroke from the hemisphere area contralaterally to a heart attack according to a method known in the literature, see Swanson et al. (A Semiautomated Method for Measuring Braln Infarct Volume, J. Cereb. Blood Flow Metabol., 10, 290-93, 1990), the disclosure of which is incorporated herein by reference. The total infarct volume was calculated by adding the damaged brain slice volume.

Cauterization of the distal part of the right MCA with temporary bilateral occlusion CCA consistently produced a well-recognizable cortical infarction in the right MCA region of each test animal. As shown in Figure 1, the area damage distribution as measured by TTC staining in each group was uniform in impact.

Figure 1 shows the results of cross-sectional measurements of infarct area distribution at representative levels along the rostrocaudal axis in the interaureal line in untreated animals and in animals treated with 10 mg / kg 3,4-dihydro-5- [4- (1-) piperidinyl) butoxy] -1 (2H) isoquinoline. The area of damage was expressed as mean ± standard deviation. Significant differences were noted between the 10 mg / kg treatment group and the control group (p <0.02, ** p <0.01, p ** <0.001). The 5 mg / kg and 20 mg / kg dose curves fall approximately halfway between the control curve and the 10 mg / kg curve, while the 40 mg / kg curve was close to the control curve. Curves for doses of 5, 20 and 40 mg / kg were omitted for clarity.

* ·

99

9

9 9 9

- 115

99,999 99 * 9 99 9

9999 999 «9999

99 99 99 99 99

Inhibition of PARP resulted in a significant reduction in the volume of damaged tissue in the 5 mg / kg dose group (106.7 ± 23.2 mm, p <0.001), in the 10 mg / kg dose group (76.4 ± 16.8 mm) , p <0.001) and 20 mg / kg (110.2 ± 42.0 mm \ p <0.01) compared to the control group (165.2 ± 34.0 mm). Data are expressed as mean + standard deviation. The significance of the differences between groups was determined using an analysis of variance (ANOVA) followed by Student's t-test for individual comparisons.

Between control and dose treated groups

There was no significant difference in mg / kg (135.6 ± 44.8 mnr). However, significant differences were found between the 5 mg / kg dose group and the 10 mg / kg dose group (p <0.02), and between the 10 mg / kg dose group and the 40 mg / kg dose group (p <0). , 01) as shown in Figure 2.

Figure 2 is a graphical representation of the effect of intraperitoneal administration of 3,4-dihydro-5- [4- (1-piperidinyl) butoxy] -1 (2H) -isoquinoline on infarct volume. Infarct volumes were expressed as mean ± standard deviation. Significant differences were noted between treatment groups and control group (p * <0.01, p ** <0.001). It is not clear why the high dose (40 mg / kg) of the 3,4-dihydro-5- [4- (1-piperidinyl) butoxy] -1 (2H) -isoquinoline PARP inhibitor was less neuroprotective. The U-dose dose response curve may indicate the dual effect of the compound.

In general, however, administration of the inhibitor in vivo resulted in a substantial reduction in infarct volume in a focal model

* 0 • 0 ♦ 0 • 000

0

116 cerebral ischemia in rats. This result shows that PARP activation plays an important role in the pathogenesis of cerebral damage in cerebral ischemia.

Arterial blood gas values (PaO ₂ , PaCO ₂ and pH) were within the physiological range in both the control and treatment groups with no significant differences in these parameters between the five groups, as shown in Table IX below. Steady state MABP was determined after completion of the surgical preparatory procedure, just prior to occlusion. MABP in ischemia was determined as the average MABP during occlusion. See Table IX below.

4

44 •

- 118 • 4 4 4 44

44 4 4 44 4 4 44 · 45 «4 4 *

TABLE IX

Pa0 ₂ (mm Hg) PaC0 ₂ (mmHg) PH MABP (mm Hg) Steady state Ischemia Control group (n = 4) 125 ± 21 38.6 ± 4.6 7.33 ± 0.05 79 ± 14 91 ± 13 ** Group treated 5 mg / kg (n = 7) 126 ± 20 38.0 ± 2.8 7.36 ± 0.02 78 ± 5 91 ± 12 ** Group treated 10 mg / kg (n = 7) 125 ± 16 39.3 ± 5.2 7.34 ± 0.03 80 ± 9 90 ± 14 * Group treated 20 mg / kg (n = 7) 122 ± 14 41.3 ± 2.8 7.35 ± 0.23 79 ± 10 91 ± 12 ** Group treated 40 mg / kg (n = 7) 137 ± 17 39.5 ± 4.7 7.33 ± 0.24 78 ± 4 88 ± 12 *

0

0 04 * 0 • 00

- 118

0 0 0 4 0 00 00

00 0 0 00 0 0 ·· 00 00 00 · 0 0 · * = significant deviation from equilibrium value, p <0.05.

** = significant deviation from equilibrium, p <0.01.

Prior to MCA and CCA occlusion, there were no significant differences in any physiological parameter between the five groups, including mean arterial blood pressure (MABP). Although MABP was significantly increased after occlusion in all five groups, MABP variations were not significant during the occlusion period between groups.

Since blood flow values obtained by laser Doppler were in relative units, only percent changes from baseline (before occlusion) are given. Occlusion of right MCA and bilaterally CCA induced a significant decrease in relative blood flow in the right parietal cortex to 20.8 ± 7.7% of baseline in the control group (n = 5), to 18.7 ± 7.4% in the 5 mg treatment group / kg (n = 7) per

21.4 ± 7.7% in the 10 mg / kg (n = 7) and na treated groups

19.3 ± 11.2% in the 40 mg / kg treatment group (n = 7). There were no significant differences in blood flow response to occlusion in the four groups. In addition, blood flow showed no significant changes in any group during the entire occlusion period.

Following the release of carotid occlusion, good recovery of blood flow (sometimes hyperaemia) in the area of true MCA was observed in all animals. Reperfusion of ischemic tissue resulted in the formation of NO and peroxynitrite, in addition to oxygen free radicals. All of these radicals have been shown to cause DNA strand breaks and activate PARP.

- 119 * · · · · 0 · 0 00 · ··· · 0 0 · · · 9 90 11 0 10 1 1 9

9 0 0 9 0 0 9 111

01 19 9 0 20

Example 5

Protection against retinal ischemia

A patient who has just been diagnosed with acute retinal ischemia is immediately administered parenterally, either by intermittent or continuous intravenous administration of a compound of the invention 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 patient's persistent neurological symptoms, the patient may optionally receive the same or another compound of the invention in the form of an additional parenteral dose. According to the invention, it is expected that there will be a significant prevention of nerve tissue damage and that the patient's neurological symptoms will be substantially reduced by administration of the compound, while the minor residual neurological sequelae of the stroke persist. In addition, it is expected that the recurrence of retinal ischemia will be prevented or reduced.

Example 6

Treatment of retinal ischemia

The patient has just been diagnosed with acute retinal ischemia. A compound of the invention of Formula I was administered parenterally immediately by a physician or nurse, either as a single dose or as a series of divided doses of the compound. The patient also received the same or different PARP inhibitor by intermittent or continuous administration via an implanted delivery system that is in the form of a biocompatible and biodegradable polymer matrix that contains a compound of the present invention of formula I, or

0 00

0 0 0

0 0 0 · 0 · 0

0 0 0 0

0 0 0 00 00

0 4 0

0 0 0

0 0 0

0 0 0

00

120 via a subdural pump inserted to deliver the compound directly to the infarct area of the brain. According to the invention, it is contemplated that the patient will recover from the coma more rapidly than if the compound of the invention were not administered. Treatment is also expected to reduce the severity of the patient's residual neurological symptoms. In addition, the recurrence of retinal ischemia is expected to be reduced.

Example 7

Protection against stroke

A patient who has just been diagnosed with an acute stroke is immediately administered parenterally, either by intermittent or continuous intravenous administration of a compound of the invention of formula I, either as a single dose or in a series of divided doses of the compound. After this initial treatment and depending on the patient's persistent neurological symptoms, the patient may optionally receive the same or another compound of the invention in the form of an additional parenteral dose. According to the invention, it is expected that there will be a significant prevention of nerve tissue damage and that the patient's neurological symptoms will be substantially reduced by administration of the compound, while the minor residual neurological sequelae of the stroke persist. In addition, it is expected that the recurrence of stroke will be prevented or reduced.

Example 8

Treatment of stroke

The patient has just been diagnosed with acute multiple stroke, and the patient was

- 121 * · • ··· • ft • ft ft ftft ftftft ftft ftftft ftft • ftftft ftftft ft ftftftft • ft ftft ftft ftft ftftftft in coma. The compound of formula (I) was administered parenterally immediately by a physician or nurse, either as a single dose or as a series of divided doses of the compound. Due to the comatose condition, the patient also receives the same or different PARP inhibitor by intermittent or continuous administration via an implanted delivery system that is in the form of a biocompatible and biodegradable polymer matrix containing a compound of formula I or via a subdural pump inserted to deliver compound directly into the heart attack area of the brain. According to the invention, it is contemplated that the patient will recover from the coma more rapidly than if the compound of the invention were not administered. Treatment is also expected to reduce the severity of the patient's residual neurological symptoms. In addition, the recurrence of stroke is expected to be reduced.

Example 9

Prevention of cardiac reperfusion injury

The patient has been diagnosed with life-threatening cardiomyopathy and needs a heart transplant. Before the donor heart is found, the patient is maintained on an Extra Corporeal Oxygenation Monitoring (ECMO) device. After the donor heart was found and the patient underwent a surgical transplant operation during which he was connected to an extracorporeal circulation device.

The patient received intracardial compound of the invention for a period of time before re-circulating his (or her) blood stream from the extracorporeal device to his (or her) new heart to prevent cardiac reperfusion injury as new heart begins to beat feefefefefefefefefefefefefefefefefefefefefefefefefefefefefffef

- 122 independently of the external device for extracorporeal circulation.

Example 10

Septic shock test

Groups of 10 male C57 / BL mice weighing 18-20 grams were administered test compound of Formula I at doses of 60, 20, 6, and 2 mg / kg daily by intraperitoneal (IP) injection for three consecutive days. In each animal, lipopolysaccharide (LPS, E. coli, LD-qq mg / animal, IV) and galactosamine (20 mg / animal, IV) were first elicited. The first dose of the test compound in a suitable vehicle was administered 30 minutes after challenge, and the second and third doses were administered 24 hours later, on the second and third days, surviving only animals receiving the second or third dose of the test compound. Mortality was recorded every 12 hours after challenge for a three-day test period.

1-Carboxynaphthalene-1-carboxamide provided protection against septic shock mortality of approximately 40%. Based on these results, other compounds of the invention are expected to provide mortality protection in excess of about 35%.

Example 11

Induce in vitro sensitivity

Human prostate cancer cell line, PC-3s, were plated in 6-well dishes and grown in monolayer cultures in RPMI1640 medium supplemented with 10% FCS. Cells are stored at 37 ° C in 5% CO 2 and 95% air. Cells were exposed to three different doses (0.1 mM to 0.1 M) prior to irradiation at a single sublethal dose level

- 123 • 4 • 44

4 4 4 4444 4444

44 44 44 44 44 PARP inhibitors, i.e. compounds of the invention of formula I as defined above. In all treatment groups, 6-well plates were exposed at room temperature in a Seifert irradiator (250 kV / 15 mA) at 0.5 mm Cu / 1 mm. Cell viability was examined by 0.4% trypan blue exclusion. Dye secretion was evaluated visually by 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 rate was calculated by the amount of 3H-thymidine incorporation after irradiation. PARP inhibitors have been shown to induce radiation sensitivity in cells.

Example 12

Induce radiation sensitivity in vivo

An effective amount of a compound or pharmaceutical composition of the present invention was administered to a patient before undergoing radiation therapy for cancer. The compound or pharmaceutical composition acted as a radiosensitizer and rendered the tumor more sensitive to radiation therapy.

Example 13

Measurement of altered gene expression in senescent cell mRNA

Human fibroblasts, Population Doubling (PDL) 94 BJ cells, were seeded in conventional growth medium, and then the medium was changed to low serum medium to achieve the physiological conditions described by Linskens et al. (Nucleic Acids Res., 23 (16), 3244-3251, 1995). DMEM / 199 supplemented with 0.5% bovine veal was used in this procedure. 9 9 9 9 9 9 9

9 99 99 999

99,999,999,999 9 • 999,999 9,999

99 99 99 99 99

- 124 serum. The cells are treated daily for 13 days with a PARP inhibitor, i.e. a compound of the invention of formula I as defined herein. Control cells were treated or untreated with the solvent used to administer the PARP inhibitor. Untreated old and young cells were tested for comparison. RNA was prepared from treated and control cells according to the techniques described in PCT International Patent Application Ser.

96/13610 by Northern blotting (membrane transfer). Probes specific for senescence-related genes were analyzed by comparing treated and control cells. In analyzing the results, the lowest level of gene expression is assigned relative number 1 to determine the basis for comparison. Three genes that are particularly related to age-related changes in the skin are collagen, collagenase and elastin. (West, Arch. Derm., 130, 87-95,

1994). Elastin expression in cells treated with a PARP inhibitor, i.e., a compound of the present invention of Formula I, was significantly increased compared to control cells. Elastin expression is significantly higher in young cells compared to senescent cells and hence treatment with a PARP inhibitor, i.e. a compound of the present invention of formula I, II, III, IV,

V, VI, VII, or VIII causes the expression levels of elastin in senescent cells to change to a level similar to that found in cells much younger. Similarly, a beneficial effect is observed for collagenase and collagen expression when treated with PARP inhibitors, i.e., a compound of the present invention of Formula I.

Example 14

Measurement of altered protein gene expression in senescent cells

- 125 0 0 0 0 ♦ 0 ♦ 0 0 0 • 0 »0 0 0 ··· 0

00 00 00 00

Approximately 10 5 BJ cells, in PDL 95-100, were seeded and grown on 15 cm dishes. The growth medium was DMEM / 199 supplemented with 10% bovine calf serum. Cells were treated daily for 24 hours with PARP inhibitors, i.e. a compound of the present invention of formula I (100 μβ / 1 milliliter of medium). Cells were washed with phosphate buffered solution (PBS), then permeabilized with 4% paraformaldehyde for 5 minutes, then washed with PBS and treated with 100% cold methanol for 10 minutes. Methanol was removed and cells were washed with PBS and then treated with 10% serum to block non-specific antibody binding.

Approximately 1 ml of the appropriate commercially available antibody solution (1: 500 dilution, Vector) was added to the cells and incubated for 1 hour. Cells were washed and washed three times with PBS. Next, a biotin labeled goat anti-mouse IgG antibody (1 ml) was added, along with 1 ml of a solution containing streptavidin conjugated to alkaline phosphatase and 1 ml of NBT reagent (Vector). Cells were washed and changes in gene expression were recorded colorimetrically. Four senescence-specific genes (collagen I, collagen III, collagenase, and interferon gamma) were examined in senescent cells treated with a PARP inhibitor compound of formula I and the results showed a decrease in interferon gamma expression, with no observable changes in expression levels of the other three genes, demonstrating that a PARP inhibitor, a compound of the present invention of formula I, can alter senescence-specific gene expression.

Example 15

Prolongation or increase in proliferative capacity and length

000

00 000 00 000 00 0 0 000 0000 0 00 0 00 00 0 · 00 00 00

- 126 cell life

To demonstrate the efficacy of the present method for prolonging the proliferative capacity and lifespan of cells, human fibroblast cell lines (either V138 in PDL 23 or BJ cells in PDL 71) were thawed and seeded into T75 vials and grown in normal medium (DMEM / M199 and 10% bovine calf serum) approximately one week at which time the cells were confluent and the cultures are ready for further division. At the time of separation, the media is aspirated and the cells are washed with phosphate buffered saline (PBS) and then treated with trypsin. Cells were counted on a Coulter counter and plated at a density of 10 cells per cm onto 6-well tissue culture plates in DMEM / 199 medium supplemented with 10% bovine calf serum and varying amounts (0.10 μΜ and 1 mM) from 100X stock solution in DMEM / M199) a PARP inhibitor, i.e. a compound of the invention of formula I, II, III, IV, V, VI, VII or VIII as defined above. This procedure was repeated every 7 days until it was apparent that the cells had stopped dividing. Untreated (control cells) reached senescence and stopped dividing after approximately 40 days of culture. Treatment with 10 μΜ 3-AB cells appears to have had little or no effect, unlike 100 μΜ 3-AB treatments that prolonged cell life and 1 mM 3-AB treatments that dramatically increased lifespan and proliferative capacity cells. Cells treated with 1 mM 3-AB were split after 60 days of culture.

Example 16

Neuroprotective Effect of Compound of Formula I on Chronic Constriction Injury (CCI) in Rats

04 ·· www -. w

0 0 · · 0 4 00 9 0 0 0

40,440 44,000 40 0 4000 0400 4044

04 04 04 00

Adult male Sprague-Dawley rats, weighing 300-350 grams, were anesthetized with intraperitoneally administered sodium pentobarbital at a dose of 50 mg / kg. Nerve ligation was performed by exposing one side of the rat sciatic nerve and dissecting a nerve segment of 5-7 mm in length and closing with four loose ligatures at 1.0-1.5 mm, followed by implantation of an intrathecal catheter and insertion of a polyethylene (PE-10) tube rinsed gentamycin sulfate into the subarachnoid space through an incision in the cistern magna. The caudal end of the catheter was gently threaded into the lumbar enlargement and the rostral end was secured with dental cement to the screw embedded in the skull and the skin incision was closed with clamps.

Thermal radiation hyperalgesia is determined using a paw withdrawal test. The rat is placed in a plastic cylinder on a 3 mm thick glass plate with a radiant heat source from a projection lamp located directly below the plantar surface of the rat's hind paw. Paw withdrawal latency is defined as the time elapsed from the start of radiant heat stimulation to withdrawal of the rat hind paw.

Mechanical hyperalgesia was determined when the rat was placed in a cage with a bottom made of perforated sheet with many small square holes. The paw withdrawal time after stabbing in the middle of the plantar surface of the rat hind paw is recorded with the tip of a safety pin inserted through the bottom of the cage.

Mechanical allodynia is determined by placing the rat in a cage similar to the cage in the previous test and applying von Frey fibers in ascending order according to the force required for

4

44

··

4 444

4 4 4

44

4 0 t

40

4 4

44

128 bends ranging from 0.07 to 76 grams per plantar surface of the rat hind paw. Von Frey fiber is used perpendicular to the skin and slowly compresses until it bends. The threshold triggering response was defined as the first strand in a row that produced at least one clear paw withdrawal from five applications.

Dark neurons, particularly in the I-II layers, were observed bilaterally in the posterior spinal cord in rats 8 days after unilateral ligation of the sciatic nerve compared to control-operated rats (mock surgery).

In this model, different doses of different compounds of the invention of formula I were tested, showing that the compounds of the invention of formula I have been shown to reduce both the incidence of dark neurons and neuropathic pain in CCI rats.

The invention has thus been described in general terms, but it will be understood that various modifications and modifications may be made thereto. These modifications do not depart from the general scope, and by their concept fall within the scope of the invention and the scope of the appended claims.

Claims (183)

PATENT CLAIMS A compound of formula I containing at least one ring nitrogen: or a pharmaceutically acceptable base or acid addition salt, hydrate, ester, solvate, prodrug, metabolite, stereoisomer, or mixtures thereof, wherein: X is a double bonded oxygen or -OH, R ² when it is present, then hydrogen or lower alkyl, Y represents the atoms necessary to form a fused monocyclic, bicyclic or tricyclic, carbocyclic or heterocyclic ring, each ring containing from 5 to 6 ring atoms, and Z is (i) -CHR ² CHR ³ - in which R ² is in the meta-position and R ³ is in the ortho-position with respect to said ring nitrogen of the general formula I, and R and R are independently hydrogen, hydroxy , amino, dimethylamino, nitro, piperidine, piperazine, imidazolidine, alkyl, aryl or aralkyl; 130 (ii) -r 6c = Cr 3 -, wherein R 1 is in the meta position relative to the ring nitrogen, and R 1 and R 2 independently represent hydrogen, lower alkyl, aryl, aralkyl, halogen, hydroxy , an amino group, a dimethylamino group, a piperidine group, a piperazine group, an imidazolidine group, an -NC2, -COOr7 group, or a -NR2R6 group in which R6 is independently hydrogen or an alkyl group containing 1 to 9 carbon atoms, or R 1 and R 2 together form a fused aromatic ring in which each individual ring contains 5 to 6 ring members, (iii) -R 1 C = N-; (iv) -CR (OH) -NR 1 -; (v) a -C (O) -Nr7- group, or (vi) a -Nr9-C (O) -CHR-LO- group in which R 1 -O is ortho to the ring nitrogen, and R 1 and R 1 -O independently represent hydrogen, lower alkyl, aryl, aralkyl, halogen, hydroxy, piperidine, piperazine, imidazolidine, -NC 2, -COOR 4 or -NR ^ R ® in which R ® independently represents a hydrogen atom or an alkyl group having 1 to 9 carbon atoms, or R 6 and R 6 ® together form a fused ring in which each individual ring contains 5 to 7 ring members, wherein said alkyl, aryl and aralkyl groups are substituted at one or more positions by hydrogen, hydroxy, halogen, haloalkyl, alkoxy, alkenoxy, alkaryloxy, aryloxy, arylalkoxy, i - 131 131 ft · cyano, amino, imine, sulfhydryl, thioalkyl, carboxy, carbocyclic, heterocyclic, lower alkyl, lower alkenyl, cycloalkyl, aryl, arylalkyl, haloaryl, amino , nitro, nitro, dimethylamino, with the following conditions: (a) when X is a double bonded oxygen and Z is -CHR CHR-, then R cannot be a hydrogen atom or a methyl group, (b) when X is a double bonded oxygen, and Z is a -R ^ C = CR &apos; -, then R can not be methyl, phenyl or a group - (CH _{2) 4} -OCH from (c) when ω and R ° together form a fused aromatic ring Y cannot be a ring selected from the group consisting of: - 132 · e e e 4 4 4 1 1 # # # # # # # # # # # # # # # (D) when X, Y and Z together form a phenanthridone, phenanthridinone, phenanthrene or phenanthridine core with an amino group or an aminoalkoxylene group at the 3-position, then the 8-position cannot also be substituted by an amino group or an aminoalkoxylene group, and (e) when X is a double bonded oxygen and Z is a six membered unsaturated ring, and Y is a phenyl group, then 2 the position of the Z-ring cannot be substituted by hydrogen or nitro, (f) when X is -OH or a double bonded oxygen, and Z is -CH = CH-, then Y is not phenyl or 5-hydroxyphenyl (g) when X is a double bonded oxygen and Z is -CH = N- then Y is not a phenyl group, and (h) when X is a double bonded oxygen, then Z is a group -C (O) NH-, then Y is not aminophen a yl group. A compound according to claim 1, wherein X is oxygen with a double bond. The compound of claim 1, wherein Y has at least one unsaturated site. A compound according to claim 1, wherein Y represents the atoms necessary to form a fused phenyl, naphthalene ring or structure. 133 The compound of claim 1, wherein Y is substituted with at least one non-hydrogen, non-interfering substituent. The compound of claim 5, wherein said substituent is selected from the group consisting of -NC 4, halogens, hydroxy, amino, dimethylamino, nitro, piperidine, piperazine, imidazolidine, aralkyl, CO Ί 11 is -COOR, -OR, and -NHR, wherein R is hydrogen, lower alkyl, or aralkyl. The compound of claim 1, wherein Z is (i) -CHR 1 CHR 1 -, (ii) -R 1 C 1 R 2 -, or (iii) -R 1 C = N-. A compound according to claim 1, wherein Z represents r π ζ «3 -R ° C = CR-, wherein R ° and R ^J together form a fused aromatic ring. The compound of claim 8, wherein said ring is substituted with at least one non-hydrogen substituent selected from the group consisting of halogens, amino, nitro, hydroxy, piperidine, piperazine, imidazolidine, dimethylamino, aryl and arylalkyl. The compound of claim 1, wherein the compound has an isoquinoline, pteridine, phenanthridine, phthalazine or quinazoline nucleus, or a tetracyclic bridged i; • 44 4 4 4 4 I 4 4 44 44 134 4 4 4 4 9 4 5 4-4 44 «4 4 4 structure to ring Y, general formula: wherein V is -O-, -S-, -NR 4, -CHO, -CHOH or -CHNH 2 in which it represents a hydrogen atom or a lower alkyl group. The compound of claim 10, wherein the compound has a phenanthridine core. The compound of claim 1, wherein the compound has a tetracyclic bridging structure to ring Y of the formula: in which : V is -CH-, X 6 is a hydrogen atom, a hydroxy group or an amino group, and X ₂ represents a hydrogen atom, an amino group, a 1-piperidine group, a 1-piperazine group, 1-imidazolidine or hydroxy. and 135 135 7 The compound of claim 1, wherein R 1, if present, is hydrogen. The compound of claim 1, wherein the compound has an IC ₅₀ for inhibiting the in vitro (ADP-ribozo) polymerase polymerase of 25 μΜ or less. The compound of claim 1, wherein: X is a double bonded oxygen, Y represents a fused benzene ring, and Z is -R ⁶ C = CR ³ -, wherein R ³ and R ⁶ together form a fused benzene ring substituted with a chloro group. The compound of claim 1, wherein: X is a double bonded oxygen, Y represents a fused benzene ring, and Z is -R ⁶ C = CR ³ - in which R ³ and R ® together form a fused benzene ring substituted with a bromo group. The compound of claim 1, wherein: X is a double bonded oxygen, Y represents a fused benzene ring substituted with -NO ₂ , and Z is -R 1 C = CR ³ -, wherein R ³ and R ⁶ together form a fused benzene ring substituted with an amino group. The compound of claim 1, wherein: X is a double bonded oxygen, Y represents a fused benzene ring, and 136 »w w« «00 00 00 00 0 0 0 0 000 00 00 0 * 0 «« 0 * 0 • · 0 0 0 0 0 0 0 0 0 0 « Z represents a group -R ^ C = CR ^ - in which R ^ and I 6 together form a fused benzene ring with a bridging substituent linking the Z ring to the Y ring. The compound of claim 1, wherein: X is a double bonded oxygen, Y is a fused benzene ring; Z represents a group -R C = CR -, wherein R ^J and R together form a fused benzene ring substituted with -no ₂ . The compound of claim 1, wherein: X is a double bonded oxygen, Y is a fused benzene ring containing at least one non-hydrogen, non-interfering substituent, and ZC Ώ O fZ Z is -R ° C = CR- in which R and R together form an unsubstituted fused benzene ring. The compound of claim 1, wherein: X is a double bonded oxygen, Y is a fused benzene ring containing at least one chlorine substituent, and Z represents a group -R ^C =CR ^ -, in which and R ^ together form a fused benzene ring substituted with a chloro group. The compound of claim 1, wherein: X is a double bonded oxygen, Y represents a fused benzene ring, and Z is -R 1 C = CR 1 -, wherein R 1 and R 2 together form a fused benzene ring substituted with -Br and -NO ₂ . • · ♦ 137 • 99 9 The compound of claim 1, wherein: X is a double bonded oxygen, Y represents a fused benzene ring, and zr o q zr Z is -R ° C = CR-, wherein R ° and R together form a fused naphthalene ring. The compound of claim 1, wherein the compound is 5 (H) 2-chloro-10-methylphenanthridin-6-one. The compound of claim 1, wherein the compound is 5 (H) 2-nitro-10-methylphenanthridin-6-one. The compound of claim 1, wherein the compound is 5 (H) 2-chloro-10-aminophenanthridin-6-one. The compound of claim 1, wherein the compound is 5 (H) 2-nitro-10-aminophenanthridin-6-one. The compound of claim 1, wherein the compound is 5 (H) 2-chloro-10-nitrophenanthridin-6-one. The compound of claim 1, wherein the compound is 5 (H) 2,10-dinitrophenanthridin-6-one. The compound of claim 1, wherein the compound is 5 (H) 2-chloro-10-hydroxyphenanthridin-6-one. The compound of claim 1, wherein the compound is 5 (H) 2-nitro-10-hydroxyphenanthridin-6-one. The compound of claim 1, wherein the compound is 5 (H) 2-chloro-10-bromophenanthridin-6-one. fc 138 • fefe • fefe · • ♦ fefe fe fefe · fe fefe «·· fefe • fe fe fefe · fefe · · The compound of claim 1, wherein the compound is 5 (H) 2-nitro-10-bromophenanthridin-6-one. The compound of claim 1, wherein the compound is 5 (H) 2-chloro-10-nitrosophenanthridin-6-one. The compound of claim 1, wherein the compound is 5 (H) 2-chloro-9,10-methylenedihydroxyphenanthridin-6-one. The compound of claim 1, wherein the compound is 5 (H) 2-nitro-9,10-methylenedihydroxyphenanthridin-6-one. 37. A pharmaceutical composition comprising a compound of formula (I) containing at least one ring nitrogen: (I) or a pharmaceutically acceptable base or acid addition salt, hydrate, ester, solvate, prodrug, metabolite, stereoisomer or mixtures thereof, wherein: X is a double bonded oxygen or -OH, if present, is hydrogen or lower alkyl, 139 0 0 0 0 • 0 0 · 0 0 0 0 0 «0 0 ♦ 0 0 1 Y represents the atoms necessary to form a fused monocyclic, bicyclic or tricyclic, carbocyclic or heterocyclic ring, each ring containing from 5 to 6 ring atoms, and Z is (i) -CHR 2 CHR 2 -, wherein R 1 is α in the meta-position and R is in the ortho-position with respect to said 9 α ring nitrogen in formula I, and R and R are independently hydrogen, hydroxy, amino, dimethylamino, nitro, piperidine, piperazine, imidazolidine (ii) a group -R ^ CMJR ^ - in which R ^ is in the meta position relative to the ring nitrogen, and R ^ and R ^ independently of one another are hydrogen, a lower alkyl group , aryl, aralkyl, halogen, hydroxy, amino, dimethylamino, piperidine, piperazine, imidazolidine, -NO 2, -COOR 4, or -NR 4 R 6, wherein R 8 is independently hydrogen or (C 1 -C 9) alkyl, or R ^D and R 3 ^{, taken} together, form a fused aromatic ring wherein each ring contains from 5 to 6 ring members; inu -R 1 C = N-; (iv) -CR 1 (OH) -NR 1 -; (v) -C (O) -NR 7, or (vi) a group -NR 9 -C (0) -CHR ®- ¹ in which R ¹ ® is in the ortho-position to the ring nitrogen, and R ^ and R ¹ independently represent a hydrogen atom, a lower alkyl group, an aryl group, an aralkyl group 00 ·· 0 0 0 0 0 0 0 0 0 0 ·· • 0 · · 140 ·· ·· 0 0 0 · • · t • 0 0 0 • 0 0 0 0 0 0 * group, halogen atom, hydroxy group, piperidino group, piperazino group, imidazolidine group, -N0 ₂ -, -CO-or -NR ^ R ^ _in which R® independently hydrogen or alkyl of 1 up to 9 carbon atoms, or R 6 and R 6 together form a fused ring wherein each individual ring contains 5 to 7 ring members, said alkyl, aryl and aralkyl group being substituted at one or more positions by hydrogen, hydroxy, halogen, haloalkyl, alkoxy, alkenoxy, alkaryloxy, aryloxy, arylalkoxy, cyano, amino, imine, sulfhydryl, thioalkyl, carboxy, carbocyclic alkyl, lower alkyl, heterocyclic, lower, cyclic, lower, arylalkyl, haloaryl an amine group, a nitro group, a nitro group, a dimethylamino group, and a pharmaceutically acceptable carrier, wherein the compound of formula I is present in an amount effective to inhibit PARP activity. 38. The pharmaceutical composition of claim 37 wherein X is oxygen with a double bond. 39. The pharmaceutical composition of claim 37 wherein Y is the atoms necessary to form a fused phenyl, naphthalene ring. - 141 • 4 4 • · »44 4 4 4 4 4 44 44 4 4 4 · 4 4 4 4 4 4 4 4 4 4 4 44 44 40. The pharmaceutical composition of claim 37, wherein Y is substituted with at least one non-hydrogen, non-interfering substituent. 41. A pharmaceutical composition according to claim 37, characterized in that Z is (i) -CHR ² CHR ³ -, (ii) a group -R-C = CR ³ -, or (iii) a group -R ² C = N -. 42. The pharmaceutical composition of claim 37, wherein Z is -R &lt; 0 &gt; C = CR- and forms a fused aromatic ring. 43. The pharmaceutical composition of claim 37, wherein said ring is substituted with at least one non-hydrogen, non-interfering substituent. 44. The pharmaceutical composition of claim 37, wherein R is hydrogen. 45. A pharmaceutical composition according to claim 37, wherein the compound has an isoquinoline, pteridine, phenanthridine, phthalazine or quinazoline core or a tetracyclic bridging structure to ring Y of the formula: • 9 142 • 9 99 • * 9 9 • 4 · 9 9 9 9 9 99 99 • 9 • 9 • 499 • 9 9 9 4 ·· · 9 4 9 9 * 9 9 9 9 9 Wherein V is -O-, -S-, -NR 4, -CHO, -CHOH or -CHNH ² wherein R ² represents a hydrogen atom or a lower alkyl group. 46. The pharmaceutical composition of claim 45, wherein the compound has phenanthridine core. 47. The pharmaceutical composition of claim 37, wherein the compound has a tetracyclic bridging structure to ring Y of the formula: in which : V is -CH-, is hydrogen, hydroxy or amino, and X ₂ represents a hydrogen atom, an amino group, a 1-piperidine group, a 1-piperazine group, 1-imidazolidine or hydroxy. 48. The pharmaceutical composition of claim 37, wherein the compound has an IC50 for inhibiting the in vitro (ADP-ribozo) polymerase polymerase of 100 μΜ or less. 49. A pharmaceutical composition according to claim 37, wherein said ftft. 143 ftft ftftftftftftft ftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftft . 50. The pharmaceutical composition of claim 37, wherein: X is a double bonded oxygen, Y represents a fused benzene ring, and zf O Q Z ' Z represents a group -R ° C = CR - in which R '' and R ° together form a fused benzene ring substituted with a chloro group. 51. The pharmaceutical composition of claim 37, wherein: X is a double bonded oxygen, Y represents a fused benzene ring, and Z is -R 1 C = CR ³ -, wherein R ³ and R ⁶ together form a fused benzene ring substituted with a bromo group. 52. The pharmaceutical composition of claim 37, wherein: X is a double bonded oxygen, Y represents a fused benzene ring substituted with a nitro group, and Z is -R 1 C = CR ³ - in which R ³ and R ³ together form a fused benzene ring substituted with an amino group. 53. The pharmaceutical composition of claim 37, wherein: X is a double bonded oxygen, Y represents a fused benzene ring, and 4 - 144 - _Λ ·· · ·· ·· * "• 44" ·· 444 * 4 · · · · · · 4 4 44 1 * 4 4 4 4 44444 »4 4 4 4444 4 * · ·· 44 44 * 4 · • 4 44 o zf in which R ³ and R ° together And o Z is -R ° C = CR-, forms a fused benzene ring with a bridging substituent linking the Z ring to the Y ring. 54. The pharmaceutical composition of claim 37, wherein: X is a double bonded oxygen, Y is a fused benzene ring, and z is o Z represents a group -R C = CR -, wherein R ^J and R ° together form a fused benzene ring substituted by -NO _second 55. The pharmaceutical composition of claim 37, wherein: X is a double bonded oxygen, Y is a fused benzene ring containing at least one non-hydrogen, non-interfering substituent, and ST Q Q Z is -R ° C = CR-, wherein R and R ° together form an unsubstituted fused benzene ring. 56. The pharmaceutical composition of claim 37, wherein: X is a double bonded oxygen, Y represents a fused benzene ring containing a chlorine substituent, and Z is -R 1 C = CR ³ - in which R ³ and R ³ together form a fused benzene ring substituted with a chloro group. 57. The pharmaceutical composition of claim 37, wherein: X is a double bonded oxygen, 9 9 9 999 145 99 99 • 9 9 9 9 9 9 99 9 • 99 999 9 9999 99 99 99 9 9 9 9 99 9 9 Y represents a fused benzene ring, and Z represents a group -R ^ C = CR ^ - in which R ^ and R ^ together form a fused benzene ring substituted by -Br and -NO2; 58. The pharmaceutical composition of claim 37, wherein: X is a double bonded oxygen, Y represents a fused benzene ring, and Z represents a group -R ^C = CR ^-, in which R ^ and R ^ together form a fused naphthalene ring. 59. The pharmaceutical composition of claim 37, wherein the compound is 5 (H) 2-chloro-10-methylphenanthridin-6-one. 60. The pharmaceutical composition of claim 37, wherein the compound is 5 (H) 2-nitro-10-methylphenanthridin-6-one. 61. The pharmaceutical composition of claim 37, wherein the compound is 5 (H) 2-chloro-10-aminophenanthridin-6-one. 62. The pharmaceutical composition of claim 37, wherein the compound is 5 (H) 2-nitro-10-aminophenanthridin-6-one. 63. The pharmaceutical composition of claim 37, wherein the compound is 5 (H) 2-chloro-10-nitrophenanthridin-6-one. A pharmaceutical composition according to claim 37 - 146 ·· 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Wherein the compound is 5 (H) 2,10-Dinitrophenanthridin-6-one. 65. The pharmaceutical composition of claim 37, wherein the compound is 5 (H) 2-chloro-10-hydroxyphenanthridin-6-one. 66. The pharmaceutical composition of claim 37, wherein the compound is 5 (H) 2-nitro-10-hydroxyphenanthridin-6-one. 67. The pharmaceutical composition of claim 37, wherein the compound is 5 (H) 2-chloro-10-bromophenanthridin-6-one. 68. The pharmaceutical composition of claim 37, wherein the compound is 5 (H) 2-nitro-10-bromophenanthridin-6-one. 69. The pharmaceutical composition of claim 37, wherein the compound is 5 (H) 2-chloro-10-nitrosophenanthridin-6-one. 70. The pharmaceutical composition of claim 37, wherein the compound is 5 (H) 2-chloro-9,10-methylenedihydroxyphenanthridin-6-one. 71. The pharmaceutical composition of claim 37, wherein the compound is 5 (H) 2-nitro-9,10-methylenedihydroxyphenanthridin-6-one. 72. The pharmaceutical composition of claim 37, wherein the composition is in the form of a capsule 00 00 0 0 0 0 • · 00 • 0 0 0 • 0 0 0 147 • 0 0 • 0 000 »0 0 00 00 Or tablets containing a single dose or divided dose of said agent, the dose being sufficient to prevent or reduce the effects of vascular stroke or other neurodegenerative disease. 73. The pharmaceutical composition of claim 37, wherein the composition is administered in the form of a sterile solution, suspension or emulsion, in a single dose or in divided doses. 74. The pharmaceutical composition of claim 37, wherein said carrier material comprises a biodegradable polymer. 75. The pharmaceutical composition of claim 74, wherein the composition is in the form of a solid implant. 76. The pharmaceutical composition of claim 74, wherein the biodegradable polymer releases the compound of Formula I over an extended period of time. 77. The pharmaceutical composition of claim 37, wherein said agent is present in an amount sufficient to treat or prevent nerve tissue damage resulting from cerebral ischemia and reperfusion injury. 78. A pharmaceutical composition according to claim 37 for the treatment or prevention of a disease or condition selected from the group consisting of tissue damage that results from 148 • fe fe fe fe fe fe cell damage or cell death due to necrosis or apoptosis, tissue damage or neuron-mediated diseases, nerve tissue damage resulting from ischemia and reperfusion injury, neurological disorders and neurodegenerative diseases, stroke, cardiovascular diseases, age-related macular degeneration, AIDS and other immune diseases senescence, arthritis, atherosclerosis, cachexia, cancer, skeletal muscle degenerative diseases including replicative senescence, diabetes, head trauma, immune senescence, inflammatory bowel disease, muscular dystrophy, osteoarthritis, osteoporosis, chronic pain, acute pain, neuropathic, acute pain, neuropathic nerve damage, peripheral nerve injury, kidney failure, retinal ischemia, septic shock and skin aging, diseases or disorders related to cell life and proliferative capacity, and diseases or disorders orbital conditions induced or exacerbated by cellular senescence or by inducing radiation sensitivity in tumor cells. 79. A pharmaceutical composition comprising a compound of formula I containing at least one ring nitrogen: (I) or a pharmaceutically acceptable base or acid addition salt, hydrate, ester, solvate, prodrug, drug prodrug, or a prodrug thereof; 149 9 9 9 9 9 9 9 9 49 99 ·· 99 • 4 9 9 • 4 9 9 • 9 9 9 • 9 9 ·· 99 metabolite, stereoisomer or mixtures thereof, in which: X is a double bonded oxygen or -OH, R ² when it is present, then hydrogen or lower alkyl, Y represents the atoms necessary to form a fused monocyclic, bicyclic or tricyclic, carbocyclic or heterocyclic ring, each ring containing from 5 to 6 ring atoms, and Z is (i) -CHR ² CHR ³ - in which R ² is in the meta-position and R ³ is in the ortho-position with respect to said ring nitrogen of the general formula I, and R and R are independently hydrogen, hydroxy , an amino group, a dimethylamino group, a nitro group, a piperidine group, a piperazine group, an imidazolidine group, an alkyl group, an aryl group or an aralkyl group, (ii) a -R ^ C = CR ³ - group in which R ^ is in meta position relative to and R ³ and R ^{6 are} independently hydrogen, lower alkyl, aryl, aralkyl, halogen, hydroxy, amino, dimethylamino, piperidine, piperazine, imidazolidine, -NO 2, -COOR ² or -NR ² R ³ in which R ³ is independently hydrogen or C 1 -C 9 alkyl, or R 1 and R ³ together form a fused aromatic ring wherein each the single ring contains 5 to 6 ring members, (iii) the group -R ² C = N-; (iv) -CR ² (OH) -NR ⁷ -; 150 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · • ·· »· and ·» < • << Wherein R @ ⁹ is hydrogen, aralkyl (v) --C (O) --NR @ ⁷ -, or (vi) --NR @ ⁹ --C (O) --CHR @ ¹⁰ -, ortho to the ring nitrogen, and R ⁹ and R ¹⁹ independently of one another denote a lower alkyl group, an aryl group, a halogen atom, a hydroxyl group, a piperidine group, a piperazine group, an imidazolidine group, a -NO ₂ -, -COOR ⁷ group or a -NR ⁷ group in which R 8 independently represents a hydrogen atom or an alkyl group containing 1 to 9 carbon atoms, or R ⁹ and R ⁹ together form a fused ring in which each individual ring contains 5 to 7 ring members, said alkyl group, aryl group and aralkyl group are substituted at one or more positions by hydrogen, hydroxy, halogen, haloalkyl, alkoxy, alkenoxy, alkaryloxy, aryloxy, arylalkoxy, cyano, amino, imine, sulfhydryl, thioalkyl, carbocyclyl, carboxy, carboxy lower alkenyl, cycloal an aryl group, an aryl group, an arylalkyl group, a haloaryl group, an amino group, a nitro group, a nitroso group, a dimethylamino group, and a pharmaceutically acceptable carrier, wherein the compound of formula I is present in an amount effective to induce neuronal activity. 80. The pharmaceutical composition of claim 79, wherein the neuronal activity is not 151 • 4 4 <4 NMDA-mediated. 81. The pharmaceutical composition of claim 79, wherein the neuronal activity is selected from the group consisting of stimulating damaged neurons, promoting neuronal regeneration, preventing neurodegeneration, and treating a neurological disorder. 82. The pharmaceutical composition of claim 81, wherein said neuronal activity is stimulation of damaged neurons due to cerebral ischemia or reperfusion injury. 83. The pharmaceutical composition of claim 81, wherein the neurological disorder is selected from the group consisting of peripheral neuropathy caused by somatic injury or disease state, traumatic head injury, somatic spinal cord injury, cerebrovascular accident associated with brain injury, demyelinating disease and neurological neurodegeneration related disorders. 84. The pharmaceutical composition of claim 83, wherein the neurodegeneration related neurological disorder is selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. 85. A pharmaceutical composition according to claim 83 for the treatment or prevention of a disease or condition selected from the group consisting of tissue damage resulting from cell damage or cell death caused by necrosis or apoptosis, tissue damage, or diseases mediated by: 0 - 152 neurons, nerve tissue damage resulting from ischemia and reperfusion injury, neurological disorders and neurodegenerative diseases, stroke, cardiovascular disease, age-related macular degeneration, AIDS and other immune diseases senescence, arthritis, atherosclerosis, cachexia, cancer , skeletal muscle degenerative diseases including replicative senescence, diabetes, head trauma, immune senescence, inflammatory bowel disease, muscular dystrophy, osteoarthritis, osteoporosis, chronic pain, acute pain, neuropathic pain, nerve injury, peripheral nerve injury, renal failure, retinal ischemia septic shock and skin aging, diseases or disorders related to cell life span or cell proliferative capacity, and diseases or conditions caused or exacerbated by cellular senescence. 86. A pharmaceutical composition comprising a compound of formula I containing at least one ring nitrogen: or a pharmaceutically acceptable base or acid addition salt, hydrate, ester, solvate, prodrug, metabolite, stereoisomer, or mixtures thereof, wherein: X is a double bonded oxygen or -OH, 153 • 99 · 9 · 9 9 · · 9 R ² when it is present, then hydrogen or lower alkyl, Y represents the atoms necessary to form a fused monocyclic, bicyclic or tricyclic, carbocyclic or heterocyclic ring, each ring containing from 5 to 6 ring atoms, and Z is (i) -CHR ² CHR ² - in which R ² is α in the meta-position and R ^j is in the ortho-position with respect to said ring nitrogen of formula I, and R and R are independently hydrogen, hydroxy, amino, dimethylamino, nitro, piperidine, piperazine, imidazolidine, an alkyl group, an aryl group or an aralkyl group, (ii) a group -R 1 C = CR ³ - in which R 1 is in the meta position with respect to the ring nitrogen, and R ² and r ⁶ independently represent a hydrogen atom, a lower alkyl group , aryl, aralkyl, halo, hydroxy, amino, dimethylamino, piperidino, piperazino group, imidazolidine group, -NO 2, -COOR ² or -NR ² R b, in which R & is independently hydrogen or alkyl containing 1 to 9 carbon atoms, or R 1 and R ² together form a fused aromatic ring in which each individual ring contains 5 to 6 ring members; -R ² C = N-; (iv) -CR ² (OH) -NR ² -; (v) -C (O) -NR ² -, or (vi) -NR ⁹ -C (O) -CHR ¹⁰ -, wherein R ¹⁰ is ortho to the ring nitrogen, and 154 and <RTIgt; 9, </RTI> 0, 0, 0, 0, and 0, 00, and R, O independently represent hydrogen, lower alkyl, aryl, aralkyl, halogen, hydroxy, piperidine, piperazine, imidazolidine, -NO 2, -COOR 4, or -NR 4 R 6, wherein R 8 is independently hydrogen or C 1 -C 9 alkyl carbon atoms, or R ¹ and R ¹ ® together form a fused ring wherein each single ring contains 5 to 7 ring members, said alkyl, aryl and aralkyl groups being substituted at one or more positions by hydrogen, hydroxy, halogen , haloalkyl, alkoxy, alkenoxy, alkaryloxy, aryloxy, arylalkoxy, cyano, amino, imine, sulfhydryl, thioalkyl, carboxy, carbocyclic a group, a heterocyclic group, a lower alkyl group, a lower alkenyl group, a cycloalkyl group, an aryl group, an arylalkyl group, a haloaryl group, an amino group, an nitro group, a nitro group, a dimethylamino group, and a pharmaceutically acceptable carrier; in an amount effective to treat inflammatory bowel diseases. 87. The pharmaceutical composition of claim 86, wherein said inflammatory bowel disease is colitis. A pharmaceutical composition according to claim 86, β - 155 ft ft ft ft ft ft ft ft ft characterized in that said inflammatory bowel disease is Crohn's disease. 89. A pharmaceutical composition comprising a compound of formula I containing at least one ring nitrogen: or a pharmaceutically acceptable base or acid addition salt, hydrate, ester, solvate, prodrug, metabolite, stereoisomer, or mixtures thereof, wherein: X is a double bonded oxygen or -OH, if present, is hydrogen or lower alkyl, Y represents the atoms necessary to form a fused monocyclic, bicyclic or tricyclic, carbocyclic or heterocyclic ring, each ring containing from 5 to 6 ring atoms, and Z is (i) the group -CHR 1 CHR ³ - in which R ³ is in the meta-position and R ³ is in the ortho-position with respect to said ring nitrogen of the general formula I, and R and R are independently hydrogen, hydroxy, amino, dimethylamino, nitro, piperidine, piperazine, imidazolidine, alkyl, aryl or aralkyl ··· 156 99 (ii) the group -R ^ C = CR ² - in which R ^ is in the meta position relative to the circular and R 6 and R 6 independently represent hydrogen, lower alkyl, aryl, aralkyl, halogen, hydroxy, amino, dimethylamino, piperidine, piperazine, imidazolidine, -NO 2, -COOR ² or --NR @ ² R @ ² in which R @ ⁵ is independently hydrogen or C1 -C9 alkyl, or r @ ^{6 and} R @ ² together form a fused aromatic ring in which each ring contains 5 to 6 ring members, (iii) -R ² C = N-; (iv) -CR ² (OH) -NR ² -; (v) -C (O) -NR ² -, or (vi) -NR ⁹ -C (O) -CHR ¹⁰ -, wherein R ¹⁰ is ortho to the ring nitrogen, and R ⁹ and R ¹⁰ independently of one another are hydrogen, lower alkyl, aryl, aralkyl, halogen, hydroxy, piperidine, piperazine, imidazolidine, -NO 2, -COOR ² or -NR ² R 6, wherein R 6 independently represents a hydrogen atom or a C 1 -C 9 alkyl group, or R ⁹ and R 6 together form a fused ring wherein each individual ring contains 5 to 7 ring members, said alkyl group, aryl group, and aralkyl are substituted at one or more positions by hydrogen, hydroxy, halogen, haloalkyl, alkoxy, alkenoxy, 157 ♦ »« 0 00 0 «• 0 0 0 0 0 0 ·· 0 0000 · φ 0 0 0 0 00 Φ 0 Φ φ 000 »» »» »» »» »» ary »ary ary ary ary ary ary ary alkaryloxy, aryloxy, arylalkoxy, cyano, amino, imine, sulfhydryl, thioalkyl, carboxy, carbocyclic, heterocyclic, lower alkyl, lower alkenyl, cycloalkyl, aryl, arylalkyl, haloaryl, amino, nitro, nitroso, dimethylamino, and a pharmaceutically acceptable carrier, wherein the compound of formula I is present in an amount effective to treat cardiovascular disorders. 90. The pharmaceutical composition of claim 89 wherein said cardiovascular disorder is selected from the group consisting of coronary artery disease, angina pectoris, myocardial infarction, cardiogenic shock, and cardiovascular tissue damage. 91. A pharmaceutical composition comprising a compound of formula I containing at least one ring nitrogen: or a pharmaceutically acceptable base or acid addition salt, hydrate, ester, solvate, prodrug, 158 · 4 · 0 · 0 · 0 440 · 444 44 0 · · 4 0 4 4 · 44 44 · 0 · metabolite, stereoisomer or mixtures thereof, in which: X is a double bonded oxygen or -OH, R ⁷ , if present, represents a hydrogen atom or a lower alkyl group, Y represents the atoms necessary to form a fused monocyclic, bicyclic or tricyclic, carbocyclic or heterocyclic ring, each ring containing from 5 to 6 ring atoms, and Z is (i) -CHR ² CHR ³ - in which R ² is in the meta-position and R ³ is in the ortho-position with respect to said ring nitrogen of the general formula I, and R and R are independently hydrogen, hydroxy , an amino group, a dimethylamino group, a nitro group, a piperidine group, a piperazine group, an imidazolidine group, an alkyl group, an aryl group or an aralkyl group, (ii) a -R ⁶ C = CR ³ - group in which R 6 is in meta position relative to and R ³ and r ^{6 are} independently hydrogen, lower alkyl, aryl, aralkyl, halogen, hydroxy, amino, dimethylamino, piperidine, piperazine, imidazolidine, -NO ₂ , - COOR ⁷ or -NR ⁷ R ® in which R ⁸ is independently hydrogen or C 1 -C 9 alkyl, or r ⁶ and R ³ together form a fused aromatic ring in which each jednotliv the single ring contains 5 to 6 ring members, (iii) the group -R ² C = N-; (iv) -CR ² (OH) -NR ⁷ -; 159 00 «« 0 0 0 0 0 0 0 0 0 0 0 0 * 00 00 00 0 0 • 0 0 0 0 0 0 <0 0 • 0 0 0 4 0 0 0 (v) -C (0) -NR 7, or (vi) a group -NR 9 -C (O) -CHR ¹ ®-, which is in the ortho-position to the ring nitrogen, and R 5 and R 10 independently of one another are hydrogen, lower alkyl, aryl, aralkyl, halogen, hydroxy, piperidine, piperazine, imidazolidine, -NO 2, -COOR 4, or -NR 4 R 6, wherein R 1 independently represents a hydrogen atom or a C 1 -C 9 alkyl group, or and R 2 O taken together form a fused ring wherein each individual ring contains 5 to 7 ring members, said alkyl group, aryl group and aralkyl group are substituted at one or more positions by hydrogen, hydroxy, halogen, haloalkyl, alkoxy, alkenoxy, alkaryloxy, aryloxy, arylalkoxy, cyano, amino, imine, sulfhydryl, alkyl, thioalkyl, heterocyclyl, carbocycle, carboxy lower alkenyl group pin, cycloalkyl, aryl, arylalkyl, haloaryl, amino, nitro, nitro, dimethylamino, and a pharmaceutically acceptable carrier, which compound is present in an amount effective to treat septic shock. 92. The pharmaceutical composition of claim 91, wherein said septic shock is 9 · 9 « 9 9 9 9 9 9 9 • 9 9 4 9 9 99 9 « 160 endotoxic shock. 93. A pharmaceutical composition comprising a compound of formula I containing at least one ring nitrogen: or a pharmaceutically acceptable base or acid addition salt, hydrate, ester, solvate, prodrug, metabolite, stereoisomer, or mixtures thereof, wherein: X is a double bonded oxygen or -OH, R ² when it is present, then hydrogen or lower alkyl, Y represents the atoms necessary to form a fused monocyclic, bicyclic or tricyclic, carbocyclic or heterocyclic ring, each ring containing from 5 to 6 ring atoms, and Z is (i) -CHR ² CHR ³ - in which R ² is in the meta-position and R is in the ortho-position with respect to said And R and R are independently hydrogen, hydroxy, amino, dimethylamino, nitro, piperidine, piperazine, imidazolidine, alkyl, aryl or aralkyl; 161 • 0 0 0 0 0 • 0 0 0 000 • 0 0 0 0 0 0 0 0 0 · · 0 • 0 · 0 0 0 0 0 • · 0 t 0 0 0 0 (Ii) a group -r 6c = Cr 3 - in which R 6 is in the meta position relative to the ring nitrogen, and R 6 and r 6 independently of one another are hydrogen, lower alkyl, aryl, aralkyl, halogen, hydroxy, amino, dimethylamino, piperidine, piperazine, imidazolidine, -NO 2, -COOR? or a group -NR 2 R 4 in which R 4 is independently hydrogen or C 1 -C 9 alkyl, X 1 Λ or R c and R c ^> together form a fused aromatic ring wherein each single ring contains 5 to 6 ring members, (iii) -R 4 C = N-; (iv) -CR 1 (OH) -NR 2 -; (v) -C (O) ~ NR - _not bo (vi) -NR ⁹ -C (O) -CHR ¹⁰ -, in which ^R10 is in the ortho-position to the ring nitrogen, and R ⁹ and R ¹⁰ independently represent hydrogen, lower alkyl, aryl, aralkyl, halogen, hydroxy, piperidine, piperazine, imidazolidine, -NO 2, -COOR? or a group -NR? R ® in which R ® independently represents a hydrogen atom or an alkyl group containing 1 to 9 carbon atoms, or R ⁹ and R ¹ ® together form a fused ring in which each individual ring contains 5 to 7 ring members wherein said alkyl, aryl and aralkyl groups are substituted at one or more positions by hydrogen, hydroxy, halogen, haloalkyl, alkoxy, alkenoxy, alkaryloxy, aryloxy, arylalkoxy, 44 ·· 162 • 4 · 4 · 44 44 44 44 44 44 4 444 4 4 4 4 4 44 444 44 4 ••• 4 4 44 4 ·· · 4 44 44 cyano, amino, imine, sulfhydryl, thioalkyl, carboxy, carbocyclic, heterocyclic, lower alkyl, lower alkenyl, cycloalkyl , aryl, arylalkyl, haloaryl, amino, nitro, nitro, dimethylamino, and a pharmaceutically acceptable carrier, wherein the compound of Formula I is present in an amount effective to treat diabetes. 94. A pharmaceutical composition comprising a compound of formula I containing at least one ring nitrogen: (I) or a pharmaceutically acceptable base or acid addition salt, hydrate, ester, solvate, prodrug, metabolite, stereoisomer or mixtures thereof, wherein: X is a double bonded oxygen or -OH, R? if present, it represents a hydrogen atom or a lower alkyl group, Y represents the atoms necessary to form a fused monocyclic, bicyclic or tricyclic, 163 000 00 0 0 000 000 0 0 000 000 0 0 0 a carbocyclic or heterocyclic ring, each individual ring containing 5 to 6 atoms as ring members, and Z is (i) -CHR ² CHR ³ - in which R ² is O is in the meta-position and R is in the ortho-position with respect to said ring nitrogen in formula I, and R and R are independently hydrogen, hydroxy, amino, dimethylamino, nitro, piperidine, piperazine, imidazolidine, an alkyl group, an aryl group or an aralkyl group, (ii) a group -R 1 C = CR ³ - in which R ⁶ is in the meta position with respect to the ring nitrogen, and R ³ and R 4 independently represent a hydrogen atom, a lower alkyl aryl, aralkyl, halogen, hydroxy, amino, dimethylamino, piperidine, piperazine, imidazolidine, -NO ₂ , -COOR ^2, or -NR ² R 6, wherein R 6 is independently hydrogen or an alkyl group containing 1 to 9 carbon atoms, or R ⁵ and R ³ together form a fused aromatic ring in which each individual ring contains 5 to 6 ring members, (iii) -R ² C = N-; (iv) -CR ² (OH) -NR ² -; (v) -C (O) -NR ² -, or (vi) -NR ⁹ -C (O) -CHR ¹⁰ -, wherein R ¹⁰ is ortho to the ring nitrogen, and R ⁹ and R ¹⁰ independently of one another represent a hydrogen atom, a lower alkyl group, an aryl group, an aralkyl group, a halogen atom, a hydroxy group, a piperidine group, a piperazine group, an imidazolidine group, • 00 • 0 • 0 164 00 00 0 0 0 f 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 -NO ₂ , -COOR? or a group -NR? R? in which R? independently represents a hydrogen atom or an alkyl group containing 1 to 9 carbon atoms, or R 6 and R 6 O together form a fused ring in which each individual ring contains 5 to 7 ring members wherein said alkyl, aryl and aralkyl are substituted at one or more positions by hydrogen, hydroxy, halogen, haloalkyl, alkoxy, alkenoxy, alkaryloxy, aryloxy, arylalkoxy, cyano, amino, amino, thio, sulfio, thio, sulfonyl carboxy, carbocyclic, heterocyclic, lower alkyl, lower alkenyl, cycloalkyl, aryl, arylalkyl, haloaryl, amino, nitro, nitro, dimethylamino, and a pharmaceutically acceptable carrier, wherein the tat The compound of formula I is present in an amount effective to treat arthritis. 95. A pharmaceutical composition comprising a compound of formula I containing at least one ring nitrogen: (I) v • · 165 ·· ··· 9 9 9 · · 99 · · 9 9 · 9 · 9 ·· 99 · 9 · 9 99 · 9 « 99 99 ·· 99 9 9 9 9 9 9 99 9 9 or a pharmaceutically acceptable base or acid addition salt, hydrate, ester, solvate, prodrug, metabolite, stereoisomer or mixtures thereof, wherein: X is a double bonded oxygen or -OH, R ² when it is present, then hydrogen or lower alkyl, Y represents the atoms necessary to form a fused monocyclic, bicyclic or tricyclic, carbocyclic or heterocyclic ring, each ring containing from 5 to 6 ring atoms, and Z is (i) -CHR ² CHR ³ - in which R ² is in the meta-position and R ² is in the ortho-position with respect to said ring nitrogen of the general formula I, and R and R are independently hydrogen, hydroxy , an amino group, a dimethylamino group, a nitro group, a piperidine group, a piperazine group, an imidazolidine group, an alkyl group, an aryl group or an aralkyl group, (ii) a -R ^ C = CR ² - group in which R ⁸ is in meta position relative to and R ² and R ⁶ independently of one another are hydrogen, lower alkyl, aryl, aralkyl, halogen, hydroxy, amino, dimethylamino, piperidine, piperazine, imidazolidine, -NO ₂ , - COOR ² or -NR ² R ⁸ , wherein R ⁸ is independently hydrogen or C 1 -C 9 alkyl, or r ⁶ and R ² together form a fused aromatic ring wherein each ý individual circle contains 5 to 6 members in the circle, 166 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 -R ² C = N-; (iv) -CR ² (OH) -NR ⁷ -; (v) -C (O) -NR ⁷ -, or (vi) -NR ⁹ -C (O) -CHR ¹⁰ -, wherein R ¹⁹ is ortho to the ring nitrogen, and R ⁹ and R ^{9 are each} independently hydrogen, lower alkyl, aryl, aralkyl, halogen, hydroxy, piperidine, piperazine, imidazolidine, -NO ₂ , -COOR ⁷ or -NR ⁷ R 8, wherein R 8 independently represents a hydrogen atom or a C 1 -C 9 alkyl group, or R ⁹ and R ⁹ together form a fused ring wherein each individual ring contains 5 to 7 ring members, said alkyl group , aryl and aralkyl are substituted at one or more positions by hydrogen, hydroxy, halogen, haloalkyl, alkoxy, alkenoxy, alkaryloxy, aryloxy, arylalkoxy, cyano, amino, imino, carbocyclyl, thioalkoxy, thioalkoxy, thioalkoxy heterocyclic, lower alkyl, lower alk enyl, cycloalkyl, aryl, arylalkyl, haloaryl, amino, nitro, nitro, dimethylamino, and a pharmaceutically acceptable carrier, wherein the compound of formula I is present in an amount effective to treat cancer. • 9 ftft 167 ·· ·· • 9 9 9,999 9 9 9 ft ft ft ft ft 96. The pharmaceutical composition of claim 95, wherein said cancer is selected from the group consisting of ACTH-producing tumors, acute lymphocytic leukemia, acute non-lymphocytic leukemia, adrenal cortex cancer, bladder cancer, brain cancer, breast cancer, uterine cancer cervical, chronic lymphocytic leukemia, chronic myelocyte leukemia, colorectal cancer, skin T cell lymphoma, endometrial cancer, esophageal cancer, Ewing's sarcoma, gallbladder cancer, hairy leukemia, neck and head cancers, Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer, , lung carcinoma (small cell and / or non-small cell), malignant peritoneal effusion, malignant pleural effusion, melanoma, mesothelioma, multiple myeloma, neuroblastoma, non-Hodgkin's lymphoma, osteosarcoma, ovarian cancer, and germ cell cancer Niku, prostate cancer, pancreatic cancer, penile cancer, retinoblastoma, skin cancer, soft tissue sarcoma, squamous cell carcinoma, stomach carcinoma, testicular cancer, thyroid, neoplasms of the trophoblast, uterine cancer, carcinoma of the vagina, carcinoma of the vulva and Vilmsova tumor. 97. A pharmaceutical composition comprising a compound of formula I containing at least one ring nitrogen: (AND) AND 168 or a pharmaceutically acceptable base or acid addition salt, hydrate, ester, solvate, prodrug, metabolite, stereoisomer, or mixtures thereof, wherein: X is a double bonded oxygen or -OH, R ² when it is present, then hydrogen or lower alkyl, Y represents the atoms necessary to form a fused monocyclic, bicyclic or tricyclic, carbocyclic or heterocyclic ring, each ring containing from 5 to 6 ring atoms, and Z is (i) -CHR ² CHR ³ - in which R ² is in the meta-position and R is in the ortho-position with respect to said ring nitrogen of the general formula I, and R and R are independently hydrogen, hydroxy, an amino group, a dimethylamino group, a nitro group, a piperidine group, a piperazine group, an imidazolidine group, an alkyl group, an aryl group or an aralkyl group, (ii) a -R ^ C = CR ³ - group in which R ^ is meta to the ring and R ³ and R ^{6 are} independently hydrogen, lower alkyl, aryl, aralkyl, halogen, hydroxy, amino, dimethylamino, piperidine, piperazine, imidazolidine, -NO 2, -COOR ² or the group -NR ² R 6, wherein R 6 is independently hydrogen or an alkyl group containing 1 to 9 carbon atoms, A 3 or R ° and R together form a fused aromatic ring in which each individual ring contains 5 to 6 ring members, 169 4 4 4 4 IH 99 * 4 4 4 9 9 9 9 9 9 4 9 9 4 9 9 9 9 t Wherein R ² is hydrogen, aralkyl (iii) -R ² C = N-; (iv) -CR ² (OH) -NR ² -; (v) a -C (O) -NR 2 -, or (vi) an -NR ⁹ -C (O) -CHR ¹⁰ -, in the ortho position to the ring nitrogen, and R ⁹ and R ¹⁰ are independently lower alkyl, aryl, halogen, hydroxy, piperidine, piperazine, imidazolidine, -NO 2, -COOR? or a group -NR 7 R 7 in which R 7 independently represents a hydrogen atom or a C 1 -C 9 alkyl group, or R ⁹ and R 6 together form a fused ring in which each individual ring contains 5 to 7 ring members, wherein said alkyl, aryl and aralkyl are substituted at one or more positions by hydrogen, hydroxy, halogen, haloalkyl, alkoxy, alkenoxy, alkaryloxy, aryloxy, arylalkoxy, cyano, amino, amino, thio, sulfhydryl, thio, sulfhydryl a carboxy group, a carbocyclic group, a heterocyclic group, a lower alkyl group, a lower alkenyl group, a cycloalkyl group, an aryl group, an arylalkyl group, a haloaryl group, an amino group, a nitro group, a nitro group, a dimethylamino group, and a pharmaceutically acceptable carrier; the compound of formula I is present in an amount effective to treat radiation sensitive tumor cells. • · 170 • · • ··· 98. The pharmaceutical composition of claim 95, wherein said tumor cells are selected from the group consisting of ACTH-producing tumors, acute lymphocytic leukemia, acute non-lymphocytic leukemia, adrenal cortex cancer, bladder cancer, brain cancer, cancer breast cancer, cervical cancer, chronic lymphocytic leukemia, chronic myelocyte leukemia, colorectal cancer, skin T cell lymphoma, endometrial cancer, esophageal cancer, Ewing's sarcoma, gallbladder cancer, hairy leukemia, neck and head cancers, Hodgkin's lymphoma, Kaposi's kidney, liver cancer, lung cancer (small cell and / or non-small cell), malignant peritoneal effusion, malignant pleural effusion, melanoma, mesothelioma, multiple myeloma, neuroblastoma, non-Hodgkin's lymphoma, osteosarcoma, ovarian cancer, carcinoma ovarian cancer, prostate cancer, pancreatic cancer, penile cancer, retinoblastoma, skin cancer, soft tissue sarcoma, squamous cell carcinoma, stomach cancer, testicular cancer, thyroid cancer, trophoblast neoplasm, uterine cancer, vaginal cancer, vulvar cancer and Vilms cancer. 99. A method of inhibiting PARP activity comprising administering a compound of Formula I containing at least one ring nitrogen: NR7 (I) • 0 0 0 0 171 90 00 or a pharmaceutically acceptable base or acid addition salt, hydrate, ester, solvate, prodrug, metabolite, stereoisomer or mixtures thereof, wherein: X is a double bonded oxygen or -OH, if present, is hydrogen or lower alkyl, Y represents the atoms necessary to form a fused monocyclic, bicyclic or tricyclic, carbocyclic or heterocyclic ring, each ring containing from 5 to 6 ring atoms, and Z is (i) the group -CHR 1 CHR 1 - in which R 1 is in the meta-position and R 1 is in the ortho-position with respect to said ring nitrogen in the general formula I, and R and R are independently hydrogen, hydroxy , an amino group, a dimethylamino group, a nitro group, a piperidine group, a piperazine group, an imidazolidine group, an alkyl group, an aryl group or an aralkyl group, (ii) a -R ⁶ C = CR ³ - group in which R ⁶ is in meta position relative to and R 6 and R 6 are independently hydrogen, lower alkyl, aryl, aralkyl, halogen, hydroxy, amino, dimethylamino, piperidine, piperazine, imidazolidine, -NO ₂ , - COOr 7 or the group -NR 6 R 6, wherein R 6 is independently hydrogen or C 1 -C 9 alkyl, or r 6 and R 6 together form a fused aromatic ring in which each The circle contains 5 to 6 members in the circle. 172 (iii) -R ² C = N-; (iv) -CR ² (OH) -NR ² -; (v) -C (O) -NR ² -, or (vi) -NR ⁹ -C (O) -CHR ¹⁰ -, wherein R ¹⁰ is ortho to the ring nitrogen, and R ⁹ and R ¹⁰ are independently hydrogen, lower alkyl, aryl, aralkyl, halogen, hydroxy, piperidine, piperazine, imidazolidine, -NO ₂ , -COOR ² or -NR ² R ⁸ wherein R ^{8 is} independently hydrogen or C 1 -C 9 alkyl, or R ⁹ and R ¹⁰ together form a fused ring wherein each ring contains 5 to 7 ring members, said alkyl group, aryl and aralkyl are substituted at one or more positions by hydrogen, hydroxy, halogen, haloalkyl, alkoxy, alkenoxy, alkaryloxy, aryloxy, arylalkoxy, cyano, amino, imine, heterocyclyl, carbocyclyl, thioalkoxy lower alkyl alkenyl, cycloalkyl, aryl, arylalkyl, haloaryl, amino, nitro, nitro, dimethylamino. 100. The method of claim 99 wherein X is oxygen with a double bond. 101. The method of claim 99, wherein Y - 173 ♦ 0 has at least one unsaturation site. 102. The method of claim 99, wherein: Y represents the atoms necessary to form a fused phenyl, naphthalene ring. 103. The method of claim 99, wherein: Y is substituted with at least one non-hydrogen, non-interfering substituent. 104. The method of claim 99, wherein Z is (i) -CHR ² CHR ³ -, (ii) a group -R-C = CR ³ -, or (iii) a group -R ² C = N- . 105. The method of claim 99, wherein zT0 Z is -R C = CR- and forms a fused aromatic ring. 106. The method of claim 99, wherein said ring is substituted with at least one non-hydrogen, non-interfering substituent. 107. The method of claim 99, characterized in that R ² if present is hydrogen. 108. The method of claim 99, wherein the compound has an isoquinoline, pteridine, phenanthridine, phthalazine or quinazoline core, or a tetracyclic bridging structure to ring Y, having the formula: • · 174 • 9 9 9 9 9 9 99 99 99 wherein V is -O-, -S-, -NR ¹ , -CHO, -CHOH or -CHNH ₂ in which R ¹ represents a hydrogen atom or a lower alkyl group. 109. The method of claim 99, wherein the compound has a phenanthridine core. 110. The method of claim 99, wherein the compound has a tetracyclic bridging structure to ring Y of the formula: in which : V is -CH-, X ₂ is hydrogen, hydroxy or amino, and X ₂ represents a hydrogen atom, an amino group, a 1-piperidine group, a 1-piperazine group, 1-imidazolidine or hydroxy. 111. The method of claim 99, wherein: 175 X is a double bonded oxygen, Y represents a fused benzene ring, and Z is -R 1 C = CR ³ - in which R ³ and R ³ together form a fused benzene ring substituted with a chloro group. 112. The method of claim 99, wherein: X is a double bonded oxygen, Y represents a fused benzene ring, and Z represents a group -R ° C = CR - in which R ^J and R ° together form a fused benzene ring substituted with a bromo group. 113. The method of claim 99, wherein: X is a double bonded oxygen, Y represents a fused benzene ring substituted with a nitro group, and Z is -R ⁶ C = CR ³ - in which R ³ and R ⁶ together form a fused benzene ring substituted with an amino group. 114. The method of claim 99, wherein: X is a double bonded oxygen, Y represents a fused benzene ring, and Z is -R 1 C = CR ³ - in which R ³ and together form a fused benzene ring with a bridging substituent linking the Z ring to the Y ring. 115. The method of claim 99, wherein: X is a double bonded oxygen, Y represents a fused benzene ring, and Z is -R ⁶ C = CR ³ - in which R ³ and R ⁶ together form a fused benzene ring substituted with - 176 • ftftft ftftft ft ·· * • ftftft ftftftftft ft ··· • ftftft ftftftft ftftftft -no ₂ . 116. The method of claim 99, wherein: X is a double bonded oxygen, Y is a fused benzene ring containing at least one non-hydrogen, non-interfering substituent, and z i and z z Z represents a group -R ° C = CR - in which R ° and R ^D together form an unsubstituted fused benzene ring. 117. The method of claim 99, wherein: X is a double bonded oxygen, Y represents a fused benzene ring containing a chlorine substituent, and a catalyst Z represents a group -R ° C = CR - in which R ^J and R ° together form a fused benzene ring substituted with a chloro group. 118. The method of claim 99, wherein: X is a double bonded oxygen, Y represents a fused benzene ring, and Z is -R 1 C = CR ³ - in which R ³ and R ³ together form a fused benzene ring substituted with -Br and -NO ₂ . 119. The method of claim 99, wherein: X is a double bonded oxygen, Y represents a fused benzene ring, and Z is -R 1 C = CR ³ - in which R ³ and together form a fused naphthalene ring. 120. The method of claim 99, wherein the compound has an IC50 for inhibiting .alpha. 177 • · 0 0 0 0 0 • 000 00 00 poles (ADP-ribozo) polymerase in vitro of 100 μΜ or less. 121. The method of claim 99, wherein the compound has an IC50 for inhibiting the in vitro (ADP-ribozo) polymerase polymerase of 25 μΜ or less. 122. The method of claim 99, wherein the compound is 5 (H) 2-chloro-10-methylphenanthridin-6-one 123. The method of claim 99, wherein the compound is 5 (H) 2-nitro-10-methylphenanthridin-6-one. 124. The method of claim 99 wherein the compound is 5 (H) 2-chloro-10-aminophenanthridin-6-one. 125. The method of claim 99, wherein the compound is 5 (H) 2-nitro-10-aminophenanthridin-6-one. 126. The method of claim 99 wherein the compound is 5 (H) 2-chloro-10-nitrophenanthridin-6-one. 127. The method of claim 99, wherein the compound is 5 (H) 2,10-dinitrophenanthridin-6-one. 128. The method of claim 99, wherein the compound is 5 (H) 2-chloro-10-hydroxyphenanthridin-6-one. 129. The method of claim 99, wherein the compound is 5 (H) 2-nitro-10-hydroxyphenanthridin-6-one. 130. The method of claim 99, wherein: 9 178 • · · · 9 The compound is 5 (H) 2-chloro-10-bromophenanthridin-6-one. 131. The method of claim 99, wherein the compound is 5 (H) 2-nitro-10-bromophenanthridin-6-one. 132. The method of claim 99, wherein the compound is 5 (H) 2-chloro-10-nitrosophenanthridin-6-one. 133. The method of claim 99, wherein the compound is 5 (H) 2-chloro-9,10-methylenedihydroxyphenanthridin-6-one. 134. The method of claim 99, wherein the compound is 5 (H) 2-nitro-9,10-methylenedihydroxyphenanthridin-6-one. 135. The method of claim 99, wherein the composition is in the form of a capsule or tablet containing a single dose or divided dose of said agent, the dose being sufficient to prevent or reduce the effects of vascular stroke or other neurodegenerative disease. 136. The method of claim 99, wherein the composition is administered in the form of a sterile solution, suspension, or emulsion, in a single dose or in divided doses. 137. The method of claim 99, wherein said composition is administered as a solid implant capable of releasing the compound for long periods of time. 138. The method of claim 99, wherein: 179 The compound is present in an amount sufficient to treat or prevent nerve tissue damage resulting from cerebral ischemia and reperfusion. injury. 139. A method of achieving neuronal activity in an animal comprising administering to said animal an effective amount of a compound of Formula I containing at least one ring nitrogen: or a pharmaceutically acceptable base or acid addition salt, hydrate, ester, solvate, prodrug, metabolite, stereoisomer, or mixtures thereof, wherein: X is a double bonded oxygen or -OH, R ⁷ , if present, represents a hydrogen atom or a lower alkyl group, Y represents the atoms necessary to form a fused monocyclic, bicyclic or tricyclic, carbocyclic or heterocyclic ring, each ring containing from 5 to 6 ring atoms, and Z is (i) -CHR ² CHR ³ - in which R ² is in the meta-position and R ³ is in the ortho-position with respect to said ring nitrogen of the general formula I, and R and R are independently hydrogen, hydroxy , amino, dimethylamino, nitro, piperidine 180 4 00 4 0 4 0 4 0 0 4 40 40 4 0 4 A group, piperazine group, imidazolidine group, alkyl group, aryl group or aralkyl group, (ii) a group -R 4 C = CR ³ - in which R ⁶ is in the meta position relative to the ring nitrogen, and R ³ and r ⁶ independently represent hydrogen, lower alkyl, aryl, aralkyl, halo, hydroxy, amino, dimethylamino, piperidino, piperazino group, imidazolidine group, -Ν0 _2, -COOR ⁷ or -NR ⁷ R ⁸ , wherein R ⁸ is independently hydrogen or C 1 -C 9 alkyl, or R 6 and R ^{3 taken} together form a fused aromatic ring wherein each ring contains 5 to 6 ring members; R ² C = N-; (iv) -CR ² (OH) -NR ⁷ -; (v) -C (O) -NR ⁷ -, or (vi) -NR ⁹ -C (O) -CHR ¹⁰ -, wherein R ¹⁰ is ortho to the ring nitrogen, and R ⁹ and R ¹⁰ independently of one another are hydrogen, lower alkyl, aryl, aralkyl, halogen, hydroxy, piperidine, piperazine, imidazolidine, -NO ₂ -, -COOR ⁷ or -NR ⁷ R ⁸ , wherein R ⁸ independently represents a hydrogen atom or a C 1 -C 9 alkyl group, or R ⁹ and R ¹⁰ together form a fused ring wherein each individual ring contains 5 to 7 ring members, said alkyl group, the aryl group and the aralkyl group are substituted on one or more 181 positions with hydrogen, hydroxy, halogen, haloalkyl, alkoxy, alkenoxy, alkaryloxy, aryloxy, arylalkoxy, cyano, amino, imine, sulfhydryl thioalkyl, carboxy, carbocyclic, heterocyclic, lower alkyl, lower alkenyl, cycloalkyl, aryl, arylalkyl, haloaryl, amino, nitro, nitro, dimethylamino. 140. The method of claim 139, wherein the neuronal activity is not NMDA-mediated. 141. The method of claim 139, wherein the neuronal activity is selected from the group consisting of stimulating damaged neurons, promoting neuronal regeneration, preventing neurodegeneration, and treating a neurological disorder. 142. The method of claim 139, wherein said neuronal activity is stimulation of damaged neurons due to cerebral ischemia or reperfusion injury. 143. The method of claim 139, wherein the neurological disorder is selected from the group consisting of peripheral neuropathy caused by somatic injury or disease state, traumatic head injury, somatic spinal cord injury, cerebrovascular accident associated with brain damage, demyelinating diseases, and neurological disorders related to neurodegeneration. 144. The method of claim 143, wherein: 9 9 9 99 182 9 9 9 9 9 9 999 9 • 9 999 99 999 99 9 99 99 99 99 99 99 99 99 neurological disorder related to neurodegeneration is selected from the group comprising Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. 145. A method of treating inflammatory bowel disorders in an animal comprising administering to said animal an effective amount of a compound of Formula I containing at least one ring nitrogen: or a pharmaceutically acceptable base or acid addition salt, hydrate, ester, solvate, prodrug, metabolite, stereoisomer, or mixtures thereof, wherein: X is a double bonded oxygen or -OH, R ² when it is present, then hydrogen or lower alkyl, Y represents the atoms necessary to form a fused monocyclic, bicyclic or tricyclic, carbocyclic or heterocyclic ring, each ring containing from 5 to 6 ring atoms, and Z is (i) -CHR ² CHR ² - in which R ² is 3 in the meta-position and R 2 is in the ortho-position with respect to said ring nitrogen in the general formula I, and R and R are independently hydrogen, hydroxy, amino, 183 ·· ·· fe # fefe fefe fefe fefefe fefefe fefefe fefefe fefefe fefefe fefe fefefe fefefe fefefe fefe fefefe fefe fefe fethye a group, a nitro group, a piperidine group, a piperazine group, an imidazolidine group, an alkyl group, an aryl group or an aralkyl group, (ii) a -R ^ C = CR ² - group in which R 6 is meta to the ring nitrogen, and R ² and r 6 are independently hydrogen, lower alkyl, aryl, aralkyl, halogen, hydroxy, amino, dimethylamino, piperidine, piperazine, imidazolidine, -NO ₂ , -COOR ² or - NR ² R ⁸ , wherein R ⁸ is independently hydrogen or C 1 -C 9 alkyl, or R 0 and R ^J together form a fused aromatic ring in which each individual ring contains 5 to 6 members in (iii) -R ² C = N-; (iv) -CR ² (OH) -NR ⁷ -; (v) -C (O) -NR ² -, or (vi) -NR ⁹ -C (O) -CHR 7 * - ⁹ -, wherein R ² ® is ortho to the ring nitrogen, and R ⁹ and R ¹⁰ independently of one another are hydrogen, lower alkyl, aryl, aralkyl, halogen, hydroxy, piperidine, piperazine, imidazolidine, -NO ₂ -, -COOR ² or -NR ² R ⁸ , wherein R ⁸ independently represents a hydrogen atom or a C 1 -C 9 alkyl group, or R ⁹ and R 6 together form a fused ring wherein each individual ring contains 5 to 7 ring members, said alkyl group, aryl group 0 * * «• 0 0 • 0 000 184 e · »0 • · 4 0 0 · 00 0 0 0 0 00 41 0 0 0 0 04 · 4 00 0 4 0 0 0 0 0 4 0 » 0 0 0 0 0 0 0 0 00 and aralkyl are substituted at one or more positions by hydrogen, hydroxy, halogen, haloalkyl, alkoxy, alkenoxy, alkaryloxy, aryloxy, arylalkoxy, cyano, amino, imine, sulfhydryl, carbocyclic, thioalkyl a lower alkyl group, a lower alkenyl group, a cycloalkyl group, an aryl group, an arylalkyl group, a haloaryl group, an amino group, a nitro group, a nitroso group, a dimethylamino group. 146. The method of claim 145, wherein said inflammatory bowel disease is colitis. 147. The method of claim 145, wherein said inflammatory bowel disease is Crohn's disease. 148. A method of treating cardiovascular disorders in an animal comprising administering to said animal an effective amount of a compound of Formula I containing at least one ring nitrogen: or a pharmaceutically acceptable base or acid addition salt, hydrate, ester, solvate, prodrug; 4 44 185 a metabolite, stereoisomer or mixtures thereof, in which: X represents a double bonded oxygen or a -OH group; R, when present, represents a hydrogen atom or a lower alkyl group, Y represents the atoms necessary to form a fused monocyclic, bicyclic or tricyclic, carbocyclic or heterocyclic ring, each ring containing from 5 to 6 ring atoms, and Z is (i) -CHR ² CHR ³ - in which R ² is in the meta-position and R ^J is in the ortho-position with respect to said ring nitrogen of the general formula I, and R and R are independently hydrogen, hydroxy , an amino group, a dimethylamino group, a nitro group, a piperidine group, a piperazine group, an imidazolidine group, an alkyl group, an aryl group or an aralkyl group, (ii) a -R ^ C = CR ³ - group in which R ^ is in meta position relative to and R ^J and R ° are each independently hydrogen, lower alkyl, aryl, aralkyl, halogen, hydroxy, amino, dimethylamino, piperidine, piperazine, imidazolidine, -NC> 2 , -COOR? or -NR? R® in which R & is independently hydrogen or alkyl containing 1-9 carbon atoms or R and R ³ together form a fused aromatic ring in which each ring contains 5 or 6 ring members, (iii) -R ² C = N-; (iv) -CR ² (OH) -NR ² -; • · 186 ··························· (V) -C (O) -NR ² -, or (vi) -NR ⁹ -C (O) -CHR ¹⁰ -, wherein R ¹⁰ is ortho to the ring nitrogen, and R ⁹ and R ¹⁰ independently of one another are hydrogen, lower alkyl, aryl, aralkyl, halogen, hydroxy, piperidine, piperazine, imidazolidine, -NO ₂ -, -COOR ² or -NR ² R 6, wherein R 7 independently represents a hydrogen atom or a C 1 -C 9 alkyl group, or R ⁹ and R ¹⁰ together form a fused ring wherein each ring contains from 5 to 7 ring members, said alkyl group, aryl and aralkyl are substituted at one or more positions by hydrogen, hydroxy, halogen, haloalkyl, alkoxy, alkenoxy, alkaryloxy, aryloxy, arylalkoxy, cyano, amino, imino, carbocyclyl, thioalkoxy, thioalkoxy heterocyclic, lower alkyl, lower and alkenyl, cycloalkyl, aryl, arylalkyl, haloaryl, amino, nitro, nitro, dimethylamino. 149. The method of claim 148, wherein said cardiovascular disorder is selected from the group consisting of coronary artery disease, angina pectoris, myocardial infarction, cardiogenic shock, and cardiovascular tissue damage. • • • 187 4 4 4 0 0 * * · ··· 150. A method of treating septic shock in an animal comprising administering to said animal an effective amount of a compound of Formula I containing at least one ring nitrogen: or a pharmaceutically acceptable base or acid addition salt, hydrate, ester, solvate, prodrug, metabolite, stereoisomer, or mixtures thereof, wherein: X is a double bonded oxygen or -OH, R, when present, represents a hydrogen atom or a lower alkyl group, Y represents the atoms necessary to form a fused monocyclic, bicyclic or tricyclic, carbocyclic or heterocyclic ring, each ring containing from 5 to 6 ring atoms, and Z is (i) -CHR ³ CHR ³ - in which R ³ is O is in the meta-position and R is in the ortho-position with respect to said ring nitrogen of the general formula I, and R and R are independently hydrogen, hydroxy, amino, dimethylamino, nitro, piperidine, piperazine, imidazolidine, an alkyl group, an aryl group or an aralkyl group, (ii) a group -R 1 C = CR ³ - in which R 1 is • 4 4 4 188 4 4 44 44 44 • 4 4 4 4 44 44 In the meta position relative to the ring nitrogen, and R ³ and r ^{6 are} independently hydrogen, lower alkyl, aryl, aralkyl, halogen, hydroxy, amino, dimethylamino, piperidine , piperazine, imidazolidine, -NO ₂ , -COOR ⁷ or -NR ⁷ R ⁸ , wherein R ⁸ is independently hydrogen or C 1 -C 9 alkyl, or R c and R ^j together form a fused an aromatic ring wherein each single ring contains 5 to 6 ring members; (iii) -R ² C = N-; (iv) -CR ² (OH) -NR ⁷ -; (v) -C (O) -NR ⁷ -, or (vi) -NR ⁹ -C (O) -CHR ¹⁹ - in which R ¹⁹ is ortho to the ring nitrogen, and R ⁹ and R ^{9 are each} independently hydrogen, lower alkyl, aryl, aralkyl, halogen, hydroxy, piperidine, piperazine, imidazolidine, -NO ₂ -, -COOR ^7, or -NR ⁷ R ⁸ in which R ⁸ independently represents a hydrogen atom or an alkyl group containing 1-9 carbon atoms or R ⁹ and R ⁹ together form a fused ring, wherein each ring contains 5 to 7 ring members, said alkyl the group, aryl and aralkyl are substituted at one or more positions by hydrogen, hydroxy, halogen, haloalkyl, alkoxy, alkenoxy, alkaryloxy, aryloxy, arylalkoxy, cyano, amino, imino, • * 9 • • 99 189 • 9 9 9 99 9 · 99 9 • 9 99 99 99 ·· 99 sulfhydryl, thioalkyl, carboxy, carbocyclic, heterocyclic, lower alkyl, lower alkenyl, cycloalkyl, aryl, arylalkyl, haloaryl, amino, nitro, nitro, dimethylamino. 151. The method of claim 150, wherein said septic shock is an endotoxic shock. 152. A method of treating diabetes in an animal comprising administering to said animal an effective amount of a compound of Formula I containing at least one ring nitrogen: or a pharmaceutically acceptable base or acid addition salt, hydrate, ester, solvate, prodrug, metabolite, stereoisomer, or mixtures thereof, wherein: X is a double bonded oxygen or -OH, R, when present, represents a hydrogen atom or a lower alkyl group, Y represents the atoms necessary to form a fused monocyclic, bicyclic or tricyclic, carbocyclic or heterocyclic ring, each of which may be: 9 ·· • 9 · ♦ 190 a single ring contains 5 to 6 atoms as ring members, and Z is (i) -CHR ² CHR ³ - in which R ² is a in the meta-position and R is in the ortho-position with respect to said ring nitrogen of the formula I, and R and R are independently hydrogen, hydroxy, amino, dimethylamino, nitro, piperidine, piperazine, imidazolidine, alkyl (ii) -R ⁸ C = CR ³ -, wherein R ⁸ is in the meta position with respect to the ring nitrogen, and R ³ and R 6 independently of each other represent a hydrogen atom, a lower alkyl group , aryl, aralkyl, halogen, hydroxy, amino, dimethylamino, piperidine, piperazine, imidazolidine, -NO ₂ , -COOR ^7, or -NR ⁷ R ⁸ , wherein R ⁸ is independently hydrogen or an alkyl group containing 1 to 9 carbon atoms, zr and or R 0 and R 2 together form a fused aromatic ring in which each individual ring contains 5 to 6 ring members, (iii) -R ² C = N-; (iv) -CR ² (OH) -NR ⁷ -; (v) -C (O) -NR ⁷ -, or (vi) -NR ⁹ -C (O) -CHR ¹⁰ -, wherein R ¹⁰ is ortho to the ring nitrogen, and R ⁹ and R ¹⁰ independently of one another are hydrogen, lower alkyl, aryl, aralkyl, halogen, hydroxy, piperidine, piperazine, imidazolidine, -NO ₂ -, -COOR ⁷ or -NR ⁷ R ⁸ in which R ⁸ ft » Ft independently represents a hydrogen atom or an alkyl group containing 1 to 9 carbon atoms, or and R ³ ® together form a fused ring in which each individual ring contains 5 up to 7 ring members wherein said alkyl, aryl and aralkyl are substituted at one or more positions by hydrogen, hydroxy, halogen, haloalkyl, alkoxy, alkenoxy, alkaryloxy, aryloxy, arylalkoxy, cyano, amino, sulfinyl, imino, imino, imino a thioalkyl group, a carboxy group, a carbocyclic group, a heterocyclic group, a lower alkyl group, a lower alkenyl group, a cycloalkyl group, an aryl group, an arylalkyl group, a haloaryl group, an amino group, a nitro group, a nitroso group, a dimethylamino group. 153. A method of treating arthritis in an animal comprising administering to said animal an effective amount of a compound of Formula I containing at least one ring nitrogen: or a pharmaceutically acceptable base or acid addition salt, hydrate, ester, solvate, prodrug, 0 · 0 00 192 • 0 0 0 0 0 0 0 0 0 · 0 000 00 0 • 00 0 0 00 0 00 00 00 00 metabolite, stereoisomer or mixtures thereof, in which: X is a double bonded oxygen or -OH, R? if present, it represents a hydrogen atom or a lower alkyl group, Y represents the atoms necessary to form a fused monocyclic, bicyclic or tricyclic, carbocyclic or heterocyclic ring, each ring containing from 5 to 6 ring atoms, and Z is (i) -CHR ² CHR 4 - in which R ² is a in the meta-position and R is in the ortho-position with respect to said ring nitrogen of the formula I, and R and R are independently hydrogen, hydroxy, amino, dimethylamino, nitro, piperidine, piperazine, imidazolidine, alkyl (ii) -R 6c = CR 3 -, wherein R 6 is in the meta position with respect to the ring nitrogen, and R 6 and R 6 independently of each other represent a hydrogen atom, a lower alkyl group, an aryl group , aralkyl, halogen, hydroxy, amino, dimethylamino, piperidine, piperazine, imidazolidine, -NO ₂ , -COOR ^7, or -NR ⁷ R ®, wherein R 8 is independently hydrogen or alkyl containing 1 to 9 carbon atoms, or r ⁶ and R ² together form a fused aromatic ring in which each individual ring contains 5 to 6 ring members; nu -R ² C = N-; (iv) -CR ² (OH) -NR ⁷ -; 0 0 0 ··· • 0 0 00 193 0 00 0 0 00 0 0 00 · 00 0 · 00 00 00 · (v) the group -C (O) -Nr 7 -, or (vi) the group -NR 4 -C (O) -CHR 4 ®-, in which R- ^θ is in the ortho position to the ring nitrogen, and R ¹ and R ¹ independently represent hydrogen, lower alkyl, aryl, aralkyl, halogen, hydroxy, piperidine, piperazine, imidazolidine, -NO ₂ -, -COOR 4 or -NR R 6, wherein R 7 independently represents a hydrogen atom or a C 1 -C 9 alkyl group, or R 6 and R 6 together form a fused ring in which each individual ring contains 5 to 7 ring members, said alkyl group , aryl and aralkyl are substituted at one or more positions by hydrogen, hydroxy, halogen, haloalkyl, alkoxy, alkenoxy, alkaryloxy, aryloxy, arylalkoxy, cyano, amino, imino, carbocyclyl, thioalkoxy, thioalkoxy, thioalkoxy heterocyclic, lower alkyl, lower alkenes alkyl, cycloalkyl, aryl, arylalkyl, haloaryl, amino, nitro, nitro, dimethylamino. 154. A method of treating cancer in an animal comprising administering to said animal an effective amount of a compound of Formula I containing at least one ring nitrogen: or a pharmaceutically acceptable base or acid addition salt, hydrate, ester, solvate, prodrug, metabolite, stereoisomer, or mixtures thereof, wherein: X is a double bonded oxygen or -OH, R, when present, represents a hydrogen atom or a lower alkyl group, Y represents the atoms necessary to form a fused monocyclic, bicyclic or tricyclic, carbocyclic or heterocyclic ring, each ring containing from 5 to 6 ring atoms, and Z is (i) -CHR ² CHR ² - in which R ² is in the meta-position and R is in the ortho-position with respect to said ring nitrogen of the general formula I, and R and R are independently hydrogen, hydroxy, an amino group, a dimethylamino group, a nitro group, a piperidine group, a piperazine group, an imidazolidine group, an alkyl group, an aryl group or an aralkyl group, (ii) a -R ^ C = CR ² - group in which R ^ is meta to the ring and R ° and R ° independently of one another are hydrogen, lower alkyl, aryl, aralkyl, halogen, hydroxy, amino, dimethylamino, piperidine, piperazine, imidazolidine, - 195 · • 0 0 • • • • 00> 0 -NO2, -COOR? or --NR? R? in which R? is independently hydrogen or C 1 -C 9 alkyl, z - o or R 0 and R together form a fused aromatic ring in which each individual ring contains 5 to 6 members in ring, (iii) -R ² C = N-; (iv) -CR ² (OH) -NR ² -; (v) a -C (O) -NR? - group, or (vi) an -NR ⁹ -C (O) -CHR ¹ ®- group in which R ¹ ® is ortho to the ring nitrogen, and R ⁹ and R ¹⁰ independently of one another are hydrogen, lower alkyl, aryl, aralkyl, halogen, hydroxy, piperidine, piperazine, imidazolidine, -NO 2 -, -COOR? or a group -NR? R ® in which R ® independently represents a hydrogen atom or an alkyl group containing 1 to 9 carbon atoms, or R ⁹ and R ¹ ® together form a fused ring in which each individual ring contains 5 to 7 ring members wherein said alkyl, aryl and aralkyl are substituted at one or more positions by hydrogen, hydroxy, halogen, haloalkyl, alkoxy, alkenoxy, alkaryloxy, aryloxy, arylalkoxy, cyano, amino, thio, imino, thio, imino, thio, amino , carboxy, carbocyclic, heterocyclic, lower alkyl, lower alkenyl, cycloalkyl, aryl, arylalkyl, haloaryl, amino, nitro, nitro, dimethylamino 4 «4 4 • 45 · 4 4 · 4 4 4 4 4 4 4 4 4 196 4 4 4 • 44 44 44 group. 155. The method of claim 154, wherein said cancer is selected from the group consisting of ACTH-producing tumors, acute lymphocytic leukemia, acute non-lymphocytic leukemia, adrenal cortex cancer, bladder cancer, brain cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia, chronic myelocyte leukemia, colorectal cancer, skin T cell lymphoma, endometrial cancer, oesophageal cancer, Ewing's sarcoma, gallbladder cancer, hairy leukemia, neck and head cancers, Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer, liver cancer carcinoma (small cell and / or non-small cell), malignant peritoneal effusion, malignant pleural effusion, melanoma, mesothelioma, multiple myeloma, neuroblastoma, non-Hodgkin's lymphoma, osteosarcoma, ovarian cancer, ovarian germ cell cancer, carcinoma in prostate, pancreatic cancer, penile cancer, retinoblastoma, skin cancer, soft tissue sarcoma, squamous cell carcinoma, stomach cancer, testicular cancer, thyroid cancer, trophoblastic neoplasm, uterine cancer, vaginal cancer, vulvar cancer, and Vilms tumor. 156. A process for preparing a compound of formula I containing at least one ring nitrogen: • 0 • 00 197 0 0 0 0 · 0 0000 0 0 0 «000 00 0 0 0 00 0 0000 0000 0 0 0 0 00 00 · 0 00 00 ·· or a pharmaceutically acceptable acid addition salt, hydrate, ester, solvate, prodrug, metabolite, a stereoisomer or mixtures thereof, in which: X is a double bonded oxygen or -OH, R, when present, represents a hydrogen atom or a lower alkyl group, Y represents the atoms necessary to form a fused monocyclic, bicyclic or tricyclic, carbocyclic or heterocyclic ring, each ring containing from 5 to 6 ring atoms, and Z is (i) -CHR ² CHR ³ - in which R ² is in the meta-position and R is in the ortho-position with respect to said 9 Q ring nitrogen in formula I, and R and R are independently hydrogen, hydroxy, amino, dimethylamino, nitro, piperidine, piperazine, piperazino, imidazolidine, alkyl, aryl or aralkyl, (ii) -R ^ C = CR ³ - in which R ^ is in the meta position relative to to the ring nitrogen, • 2 Zr and R ^J and R ^{D are} independently hydrogen, lower alkyl, aryl, aralkyl, halo, hydroxy, amino, dimethylamino, piperidino, piperazino group, imidazolidine group, -NO ₂ , -COOR ² or -NR ² R ® in which R ® independently represents a hydrogen atom or an alkyl group containing 1 to 9 carbon atoms; wherein each individual circle contains 5 to 6 members in the circle, 198 (iii) -R ² C = N-; (iv) -CR ² (OH) -NR ⁷ -; (v) a -C (O) -NR ⁷ - group, or (vi) an -NR ⁹ -C (O) -CHR-Ιθ- group in which R 6 is ortho to the ring nitrogen, and R ⁹ and R ¹¹ independently represent hydrogen, lower alkyl, aryl, aralkyl, halogen, hydroxy, piperidine, piperazine, imidazolidine, -NO ₂ , -COOR ⁷ or -NR ⁷ R ⁸ , wherein R ⁸ independently represents a hydrogen atom or a C 1 -C 9 alkyl group, or R ⁹ and R 6 together form a fused ring wherein each ring contains 5 to 7 ring members, said alkyl group, aryl and aralkyl are substituted at one or more positions by hydrogen, hydroxy, halogen, haloalkyl, alkoxy, alkenoxy, alkaryloxy, aryloxy, arylalkoxy, cyano, amino, imine, heterocyclyl, carbocyclyl, thioalkoxy lower alkyl, lower and lower alkyl alkenyl, cycloalkyl, aryl, arylalkyl, haloaryl, amino, nitro, nitro, dimethylamino, the process comprising the step of reacting a compound of formula IV: (IV) - 199 ftftft ftft ftft ftft ftftftftft ftft ftft ftft ftft ftft ftft ftft ft ftft ft with nitrogen reagent, to form a compound of formula V: 157. The method of claim 156, wherein the compound has an IC50 for inhibiting poles of (ADP-ribozo) polymerase in vitro of 100 μΜ or less. 158. The method of claim 156, wherein the compound has an IC50 for inhibiting the in vitro (ADP-ribozo) polymerase polymerase of 25 μΜ or less. 159. The method of claim 156, wherein: X is a double bonded oxygen, Y represents a fused benzene ring, and Z is -R 1 C = CR ³ - in which R ³ and R ³ together form a fused benzene ring substituted with a chloro group. 160. The method of claim 156, wherein: X is a double bonded oxygen, Y represents a fused benzene ring, and Z is -R 1 C = CR ³ - in which R ³ and R ³ together form a fused benzene ring substituted with a bromo group. 161. The method of claim 156, wherein: X represents oxygen with double bond, • 444 • 444 200 4444 4444 4444 44 44 44 44 44 Y represents a fused benzene ring substituted with -NO ₂ , and Z is -R ⁹ C = CR ³ -, wherein R ³ and R ⁹ together form a fused benzene ring substituted with an amino group. 162. The method of claim 156, wherein: X is a double bonded oxygen, Y represents a fused benzene ring, and Z represents a -R ° C = CR- group in which R ^J and R ° together form a fused benzene ring with a bridging substituent linking the Z ring to the Y ring. 163. The method of claim 156, wherein: X is a double bonded oxygen, Y represents a fused benzene ring, and Z is -R 1 C = CR ³ -, wherein R ³ and R ⁹ together form a fused benzene ring substituted with -no ₂ . 164. The method of claim 156, wherein: X is a double bonded oxygen, Y is a fused benzene ring containing at least one non-hydrogen, non-interfering substituent, and Z is -R ⁶ C = CR ³ - in which R ³ and R ⁶ together form an unsubstituted fused benzene ring. 165. The method of claim 156, wherein: X is a double bonded oxygen, Y is a fused benzene ring containing at least one chlorine substituent, and Z represents a group -R ⁶ C = CR ³ - in which R ³ and R ⁶ together • 9 • ·· 201 99 9 99 99 9 99 99 forms a fused benzene ring substituted with a chloro group. 166. The method of claim 156, wherein: X is a double bonded oxygen, Y represents a fused benzene ring, and Z is -R 1 C = CR ³ - in which R ³ and R ³ together form a fused benzene ring substituted with -Br and -NC 4. 167. The method of claim 156, wherein: X is a double bonded oxygen, Y represents a fused benzene ring, and Z is -R 1 C = CR ³ - in which R ³ and R ³ together form a fused naphthalene ring. 168. The method of claim 156, wherein the compound is 5 (H) 2-chloro-10-methylphenanthridin-6-one. 169. The method of claim 156, wherein the compound is 5 (H) 2-nitro-10-methylphenanthridin-6-one. 170. The method of claim 156, wherein the compound is 5 (H) 2-chloro-10-aminophenanthridin-6-one. 171. The method of claim 156, wherein the compound is 5 (H) 2-nitro-10-aminophenanthridin-6-one. 172. The method of claim 156, wherein the compound is 5 (H) 2-chloro-10-nitrophenanthridin-6-one. 173. The method of claim 156, wherein the compound is 5 (H) 2,10-dinitrophenanthridin-6-one. - 202 174. The method of claim 156, wherein the compound is 5 (H) 2-chloro-10-hydroxyphenanthridin-6-one. 175. The method of claim 156, wherein the compound is 5 (H) 2-nitro-10-hydroxyphenanthridin-6-one. 176. The method of claim 156, wherein the compound is 5 (H) 2-chloro-10-bromophenanthridin-6-one. 177. The method of claim 156, wherein the compound is 5 (H) 2-nitro-10-bromophenanthridin-6-one. 178. The method of claim 156, wherein the compound is 5 (H) 2-chloro-10-nitrosophenanthridin-6-one. 179. The method of claim 156, wherein the compound is 5 (H) 2-chloro-9,10-methylenedihydroxyphenanthridin-6-one. 180. The method of claim 156, wherein the compound is 5 (H) 2-nitro-9,10-methylenedihydroxyphenanthridin-6-one. 181. The method of claim 156, wherein said nitrogen introducing agent is a mixture of NaN4 and a strong acid. 182. The method of claim 181, wherein said acid is sulfuric acid. - 203 ·· 00 ·· 00 00 00 0 0 0 0 000 0000 0 0 00 0 0 000 0 00 0 0 000 000 00 000 00 0 0 0 0 0 0 0 0 0 0 00 00 00 00 00 00 183. The compounds, compositions, methods and methods described herein. Represented by: Dr. Miloš Všetečka 1/2 Fig. 1 Damaged area (mm ^z ) Distance from interaur line (mm) Control (n = 14) Treatment group, dose 10 mg / kg (n = 7)