MXPA06006255A - 6-substituted 2-quinolinones and 2-quinoxalinones as poly(adp-ribose) polymerase inhibitors - Google Patents

Abstract

The present invention provides compounds of formula (I), their use as PARP inhibitors as well as pharmaceutical compositions comprising said compounds of formula (I) wherein n, R1, R2, R3, R4, and X have defined meanings.

Description

2-QUINOLINONES AND 2-CHLNOXALINONES 6-SUBSTITUTED AS POLYMER INHIBITORS (ADENOSINDIFOSFO-RIBOSA) POLYMERASE FIELD OF THE INVENTION The present invention relates to inhibitors of PARP and provides compounds and compositions containing the described compounds. In addition, the present invention provides methods of using the described PARP inhibitors, for example as a medicine.

BACKGROUND OF THE INVENTION The nuclear enzyme poly (ADP-ribose) polymerase 1 (PARP-1) is a member of the PARP family of enzymes, which consists of PARP-1 and several novel poly (ADP-ribosilant) enzymes recently identified. PARP is also referred to as poly (adenosine-5-diphospho-ribose) polymerase or PARS (poly (ADP-ribose) synthetase). PARP 1 is a nuclear protein greater than 116 kDa consisting of 3 domains: the N-terminal DNA binding domain containing two zinc fingers, the self-modifying domain, and the C-terminal catalytic domain. It is present in almost all eukaryotes. The enzyme synthesizes poly (ADP-ribose), a branched polymer that can consist of more than 200 units of ADP-ribose. The protein receptors of poly (ADP-ribose) are directly or indirectly involved in the maintenance of DNA integrity. They include histones, topoisomerases, DNA and RNA polymerases, DNA ligases and Ca2 + and Mg2 + -dependent endonucleases. The PARP protein is highly expressed in many tissues, most notably in the immune system, heart, brain, and germline cells. Under normal physiological conditions, there is minimal activity of PARP. However, DNA damage causes immediate activation of PARP up to 500 times. Among the many functions attributed to PARP, and especially to PARP-1, are its main function of facilitating DNA repair by means of ADP-ribosylation and therefore of coordinating several DNA repair proteins. As a result of the activation of PARP, the concentration of NAD + declines significantly. The extensive activation of PARP leads to severe depletion of NAD + in cells suffering from massive DNA damage. The short half life of poly (ADP-ribose) results in a high turnover rate. Once poIi (ADP-ribose) is formed, it is rapidly degraded by the constitutively active poly (ADP-ribose) glycohydrolase (PARG), together with phosphodiesterase and (ADP-ribose) protein lyase. PARP and PARG form a cycle that converts a large amount of NAD + into ADP-ribose. In less than one hour, overstimulation of PARP can cause a fall of NAD + and ATP to less than 20% of the normal concentration. This scenario is especially damaging during ischemia, when oxygen deprivation has already dramatically compromised cellular energy performance. It is assumed that the subsequent production of free radicals during reperfusion is a major cause of tissue damage. Part of the fall of ATP, which is typical in many organs during ischemia and reperfusion, could be associated with NAD + depletion due to the replacement of poly (ADP-ribose). In this way, it is expected that the inhibition of PARP or PARG retains cellular energy in its range, thus enhancing the survival of ischemic tissues after the attack. The synthesis of poly (ADP-ribose) is also involved in the induced expression of several genes essential for the inflammatory response. PARP inhibitors suppress the production of inducible nitric oxide synthase (NOS) in macrophages, P-type selectin and intercellular adhesion molecule-1 (ICAM-1) in endothelial cells. This activity supports the strong anti-inflammatory effects exhibited by the PARP inhibitors. The inhibition of PARP is able to reduce necrosis by preventing the translocation and infiltration of neutrophils into damaged tissues. PARP is activated by damaged DNA fragments and, once activated, catalyzes the binding of up to 100 units of ADP-ribose with a variety of nuclear proteins, including histones and PARP itself. During most cellular efforts, extensive activation of PARP can rapidly lead to cell damage or death by depletion of energy stores. As four ATP molecules are consumed per regenerated NAD + molecule, NAD + is depleted by massive activation of PARP; In the effort to resynthesize the NAD +, also the ATP can be exhausted. PARP activation has been reported to play a key role in the neurotoxicity induced by NMDA and NO. This has been demonstrated in cortical cultures and in hippocampal slices where the prevention of toxicity is directly correlated with the potency of PARP inhibition. Thus, the potential role of PARP inhibitors in the treatment of neurodegenerative diseases and head trauma has been recognized, although the exact mechanism of action has not yet been elucidated. "Similarly, it has been shown that simple injections of PARP inhibitors have reduced the size of the infarction caused by ischemia and reperfusion of the heart or skeletal muscle in rabbits In these studies, a single injection of 3-amino-benzamide (10 mg / kg), either one minute before the occlusion or one minute after of reperfusion, causes similar reductions in infarct size in the heart (32-42%), while 1,5-dihydroxyisoquinoline (1 mg / kg), another PARP inhibitor, reduced the infarct size to a comparable degree (38-48%) These results make it reasonable to assume that PARP inhibitors could save the previously ischemic heart or the reperfusion injury of skeletal muscle tissue. It can also be used as a measure of damage after neurotoxic attacks that originate from exposure to any of the following glutamate-type inducers (by stimulation of the NMDA receptor), reactive oxygen intermediates, amyloid-β protein, N-methyl -4-phenyl-1, 2,3,6-tetrahydropyridine (MPTP) or its active metabolite N-methyl-4-phenylpyridine (MPP +), which participates in pathological conditions such as stroke, Alzheimer's disease and Parkinson's disease. Other studies continue to explore the role of PARP activation in cerebellar granule cells in vitro and in the neurotoxicity of MPTP. Excessive neural exposure to glutamafo, which serves as the predominant neurotransmitter in the central nervous system and acts on N-methyl-D-aspartate (NMDA) receptors and other receptor subtypes, occurs most frequently as a result of a stroke or other neurodegenerative processes. Oxygen-deprived neurons release glutamate in large amounts during an ischemic attack of the brain, for example during a stroke or heart attack. In turn, this excessive release of glutamate causes overstimulation (excitotoxicity) of N-methyl-D-aspartate (NMDA), AMPA, kainate and MGR receptors, which open the ion channels and allow the uncontrolled flow of ions ( for example Ca2 + and Na + into cells, and K + out of cells), leading to an overstimulation of neurons. Overstimulated neurons secrete more glutamate, creating a feedback loop or domino effect that eventually produces cell damage or death by production of proteases, lipases and free radicals. Excessive activation of glutamate receptors has been implicated in several diseases and neurological 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, hypoglycaemia, ischemia, trauma and nervous attack. Exposure to glutamate and consequent stimulation have also been implicated as a basis for compulsive disorders, particularly substance dependence. The evidence includes findings in many animal species, as well as in brain cortical cultures treated with glutamate or NMDA, that glutamate receptor antagonists (ie, compounds that block glutamate binding to its receptor or activation of its receptor), prevent neural damage after vascular attack. Attempts to prevent excitotoxicity by blocking NMDA receptors, AMPA, kainate and MGR, have been difficult because each receptor has multiple sites in which glutamate can bind, and therefore it has been difficult to find a universal antagonist or a mixture of effective antagonists to prevent the binding of glutamate to all the receivers and be able to prove this theory. In addition, many of the compositions that are effective in blocking the receptors are also toxic to animals. Therefore, there is currently no known effective treatment for glutamate abnormalities. The stimulation of NMDA receptors with glutamate, for example, activates the enzyme neuronal nitric oxide synthase (nNOS), leading to the formation of nitric oxide (NO), which also intervenes in neurotoxicity. The neurotoxicity of NMDA can be prevented by treatment with nitric oxide synthase (NOS) inhibitors, or by means of directed genetic interruption of nNOS in vitro. Another use of PARP inhibitors is the treatment of peripheral nerve lesions and the resulting pathological pain syndrome, known as neuropathic pain, for example that induced by chronic constriction injury (CCI) of the common sciatic nerve, and in which it occurs Trans-synaptic alteration of the dorsal horn of the spinal cord, characterized by hyperchromatosis of the cytoplasm and nucleoplasm (the so-called "dark" neurons). There is also evidence that PARP inhibitors are useful in the treatment of inflammatory bowel disorders, such as colitis. Specifically, colitis was induced in rats by intraluminal administration of 50% nitrobenzenesulfonic acid hapten in ethanol. The treated rats received 3-aminobenzamide, a specific inhibitor of PARP activity. The inhibition of PARP activity reduced the inflammatory response and restored the morphology and energy status of the distant colon. Additional evidence suggests that PARP inhibitors are useful in treating arthritis. In addition, it seems that PARP inhibitors are useful for treating diabetes. It has been shown that PARP inhibitors are useful in the treatment of endotoxic shock or septic shock. PARP inhibitors have also been used to prolong the lifespan and proliferative capacity of cells, which includes the treatment of diseases such as skin aging, Alzheimer's disease, atherosclerosis, osteoarthritis, osteoporosis, muscular dystrophy, Degenerative diseases of skeletal muscle that involve replicative senescence, muscular degeneration related to aging, immune senescence, AIDS and other diseases of immune senescence; and to alter the genetic expression of senescent cells. It is also known that PARP inhibitors, such as 3-amino-benzamide, affect the general repair of DNA in response for example to hydrogen peroxide or ionizing radiation. The pivotal role of PARP in repairing DNA strand breaks is well established, especially when caused directly by ionizing radiation, or indirectly after enzymatic repair of DNA lesions induced by methylation agents, topoisomerase I inhibitors and other chemotherapeutic agents such as cisplatin and bleomycin. A variety of studies using knockout mice, trans-dominant inhibition models (overexpression of the DNA binding domain), antisense and low molecular weight inhibitors, have demonstrated the role of PARP in cell repair and survival after of induction of DNA damage. The inhibition of the enzymatic activity of PARP would lead to a greater sensitivity of the tumor cells towards treatments that damage the DNA. PARP inhibitors have been reported to be effective in the (hypoxic) radiosensitization of tumor cells, and are effective in preventing the recovery of tumor cells from potentially lethal and sublethal damage to their DNA after radiation therapy, presumably for its ability to prevent DNA chain breaks from being repaired, and affecting several signaling pathways of DNA damage. - PARP inhibitors have been used to treat cancer. In addition, the US patent. No. 5,177,075 describes various isoquinolines used to increase the lethal effects of ionizing radiation or chemotherapeutic agents on tumor cells. Weltin et al., "Effect of 6- (5-Phenanthridinone, an Inhibitor of Poly (ADP-ribose) Polymerase, on Cultured Tumor Cells," Oncol. Res., 6: 9, 399-403 (1994), describe inhibition. of PARP activity, reduced proliferation of tumor cells, and remarkable synergistic effect when tumor cells are co-treated with an alkylating agent.A recent and comprehensive review of the state of the art was published by Li and Zhang in IDrugs 2001 , 4 (7): 804-812 The need for effective and potent PARP inhibitors, and more particularly for PARP-1 inhibitors that produce minimal side effects, continues The present invention provides compounds, compositions and methods for inhibiting the activity of PARP, to treat cancer or prevent damage to cells, tissues or organs arising from cell damage or death, due for example to necrosis or apoptosis The compounds and compositions of the present invention are especially useful for incrr Increase the effectiveness of chemotherapy and radiotherapy, where a main effect of the treatment is to damage the DNA of the target cells.

Prior art EP 371564, published June 6, 1990, describes quinoline, quinazoline or quinoxaline derivatives, substituted with (1 H-azol-1-methylmethyl). The described compounds suppress the elimination in the plasma of the retinoic acids. More particularly, the compounds 3-ethyl-6- [2-methyl-1- (1H-1, 2,4-triazol-1-yl) propyl] -2 (1 H) -quinoxalinone (compound No. 20 in the present application), 3-ethyl-6- [1 - (1 H -imidazol-1-yl) -2-methylpropyl] -2 (1 H) -quinoxalinone (compound No. 21 in the present application), 6- [2-methyl-1- (1H-1, 2,4-triazol-1-yl) propyl] -3- (2-thienyl) -2 (1H) -quinoxalinone (compound No. 22 in the present application ), 6- [2-methyl-1- (1rV-1, 2,4-triazol-1-yl) propyl] -3- (thienyl) -2 (1 / - /) - quinoxalinone (compound No. 23 in the present application), 6- [1- (1H-imidazol-1-yl) -2-methylpropyl] -3- (3-thienyl) -2 (1 - /) -quinoxalinone (compound No. 24 in the present application ) and 6- [1- (1H-imidazol-1-yl) pentyl] -3-methyl-2 (1H) -quinoxalinone (compound No. 25 in the present application).

DETAILED DESCRIPTION OF THE INVENTION This invention relates to the compounds of formula (I): the? / - forms, the addition salts and the stereochemically isomeric forms thereof, wherein: n is O, 1 or 2; X is N or CR5, wherein R5 is hydrogen, or together with -R1 can form a bivalent radical of formula -CH = CH-CH = CH-; R1 is C-? 6 alkyl or thienyl; R2 is hydrogen or hydroxy, or together with R3 or R4 can form = 0; - R3 is a radical selected from: - (CH2) S-NR6R7 (a-1), -0-H (a-2), -O-R8 (a-3), -S-R9 (a-4) , or -C = N (a-5), where: s is 0, 1, 2 or 3; R6 is -CHO, C1-6alkyl, hydroxyC1-6alkyl, alkyl (C6-6) -carbonyl, di (C1-6alkyl) -amino-C1-6alkyl, alkyloxy ( C? -6) -alkyl of Ci. 6) C 1-6 alkylcarbonylamino C? -6 alkyl, piperidinyl-alkyl (C? -6) -aminocarbonyl, piperidinyl, piperidinyl-C 1-6 alkyl, piperidinyl-alkyl (C? 6) aminocarbonyl, C? -6 alkyloxy, thienyl-C1-6 alkyl. pyrrolyl-C 1-6 alkyl, aryl-C 1-6 -piperidinyl, arylcarbonyl C 1-6 alkyl, arylcarbonylpiperidinyl C 1-6 alkyl, haloindozolylpiperidinyl C 1-6 alkyl, or aryl-alkyl (C? -6) - (C-6 alkyl) -amino-aikyl of Ci-β; R7 is hydrogen or d-6 alkyl; R8 is C1-6 alkyl, alkyl (C6-6) carbonyl or di (C1-6 alkyl) -amino-C6-alkyl; and R9 is di (C6-alkyl) -amino-alkyl or R3 is a group of the formula: -Z- (b-1), wherein: Z is a heterocyclic ring system selected from: (c-l) (e-2) (c-3) í wherein each R10 is, independently, hydrogen, C-? -6 alkyl, aminocarbonyl, hydroxy, iiU alkane Cj. (C 1-6) alkyloxy-C 1-6 alkyl, C 1-6 alkyloxy-C 1-6 alkylamino, aryl-C? -6 alkyl, di (phenyl) C 2-6 alkenyl ), piperidinyl-C? -6 alkyl, C3-10 cycloalkyl, (C3-? o) cycloalkyl-C-? 6 alkyl, aryloxy (hydroxy) -C? -6 alkyl, haloindazolyl, aryl-alkyl of C? -6, C2-6 aryl-alkenyl, morpholino, alkyl (C? -6) -imidazolyl, or pyridinyl-alkyl (C? 6) amino; R 4 is hydrogen, C 6 alkyl, furanyl, pyridinyl, aryl alkyl '1-6 aryl is phenyl or phenyl substituted with halogen, C 1-6 alkyl or C? -6 alkyloxy; with the proviso that: when n is 0, X is N, R2 is hydrogen, R3 is a group of formula (b-1), Z is the heterocyclic ring system (c-2) or (c-4), wherein said heterocyclic ring system Z is attached to the rest of the molecule with a nitrogen atom, and R10 is hydrogen; then R4 is different from C-? -6 alkyl or pyridinyl. Provided that the heterocyclic ring system Z contains a portion -CH2-, -CH = or -NH-, the substituent R10 or the rest of the molecule can be attached to the carbon or nitrogen atom, in which case one or both of the atoms of hydrogen are replaced. The compounds of formula (I) may also exist in their tautomeric forms. Although these forms are not explicitly indicated in the above formula, they are considered to be included within the scope of the present invention. Several terms used in the above definitions and also later, will be explained below. These terms are sometimes used as such or in combination terms. As used in the present disclosure, halo is a generic of fluorine, chlorine, bromine and iodine; C? -6 alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms, such as for example methyl, ethyl, propyl, butyl, pentyl, hexyl, 1-methylethio, 2-methylpropyl, 2-methyl-butyl, 2-methylpentyl and the like; alkanediyl of C -? - 6 defines bivalent straight and branched chain saturated hydrocarbon radicals, having from 1 to 6 carbon atoms, such as for example methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4 -butanediyl, 1,5-pentanediyl, 1,6-hexanediyl and its branched isomers such as 2-methylpentanediyl, 3-methylpentanediyl, 2,2-dimethylbutanediyl, 2,3-dimethylbutanediyl and the like; C2-β alkenyl defines straight and branched chain hydrocarbon radicals containing a double bond and having from 2 to 6 carbon atoms, such as for example ethenyl, 2-propenyl, 3-butenyl, 2-pentenyl, -pentenyl, 3-methyl-2-butenllo, and the like; C3-? 0 cycloalkyl includes cyclic hydrocarbon groups having from 3 to 10 carbons, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl and the like. The term "addition salt" comprises the salts which the compounds of formula (I) can form with organic or inorganic bases such as amines, alkali metal bases and alkaline earth metal bases, or quaternary ammonium bases, or with organic acids or inorganic such as mineral acids, sulfonic acids, carboxylic acids or acids containing phosphorus. The term "addition salt" also comprises the pharmaceutically acceptable salts, metal complexes and solvates, and salts thereof, which the compounds of formula (I) are capable of forming. The term "pharmaceutically acceptable salts" means pharmaceutically acceptable acid or base addition salts. It is understood that these pharmaceutically acceptable acid or base addition salts comprise the non-toxic forms of the therapeutically effective acid and base addition salts, which the compounds of formula (I) are capable of forming. The compounds of formula (I) having basic properties can be converted into their pharmaceutically acceptable acid addition salts by treating the base form with an appropriate acid. Suitable acids comprise, for example, inorganic acids, such as hydrohalic acids, for example hydrochloric or hydrobromic acid; sulfuric, nitric, phosphoric acid and the like; or organic acids such as acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic (ie, butanedioic), maleic, fumaric, malic, tartaric, citric, methanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclic, salicylic, pamoico, and similar. The compounds of formula (I) having acidic properties can be converted into their pharmaceutically acceptable base addition salts by treating said acid form with a suitable organic or inorganic base. Suitable base salt forms comprise, for example, the ammonium salts; the alkali metal and alkaline earth metal salts, for example the lithium, sodium, potassium, magnesium, calcium salts and the like; salts with organic bases, for example the benzathine,? / - methyl-D-glucamine, hydrabamine salts; and salts with amino acids such as for example arginine, lysine and the like. The terms "acid addition salt" or "base" also comprise the hydrates and the solvent addition forms that the compounds of formula (I) can form. Examples of such forms are hydrates, alcoholates and the like. The term "metal complexes" means a complex formed between a compound of formula (I) and one or more organic or inorganic metal salts. Examples of said organic or inorganic salts include halides, nitrates, sulfates, phosphates, acetates, trifluoroacetates, trichloroacetates, propionates, tartrates, sulfonates; for example methylsulfonates, 4-methyl-phenyl-sulfonates, salicylates, benzoates and the like, of the metals of the second main group of the periodic system, for example the magnesium or calcium salts, or the third or fourth main group, for example aluminum, tin, lead , as well as the first to the eighth transition group of the periodic system, such as for example chromium, manganese, iron, cobalt, nickel, copper, zinc and the like. The term stereochemically isomeric forms of the compounds of formula (I) used above, defines all possible compounds of formula (I), formed of the same atoms linked by the same sequence of bonds but having different three-dimensional structures that are not interchangeable. Unless otherwise mentioned or indicated, the chemical designation of a compound encompasses the mixture of all possible stereochemically isomeric forms that said compound may have.1 Such a mixture may contain all diastereomers or enantiomers of the basic molecular structure of said compound. compound. All stereochemically isomeric forms of the compounds of formula (I), both in pure form and in admixture with one another, are encompassed within the scope of the present invention. The? -oxide forms of the compounds of formula (I) comprise those compounds of formula (I) wherein one or more nitrogen atoms are oxidized to form the so-called? / -oxide, particularly those? / - oxides wherein one or more of the pyridine, piperazine, or pyridazinyl nitrogens are? / -oxidized. Hereinafter, whenever the term "compounds of formula (I)" is used, it also includes the? / -oxide forms, the pharmaceutically acceptable acid or base addition salts and all stereoisomeric forms. The compounds described EP 371564 suppress the elimination of retinoic acids from plasma. The compounds 3-ethyl-6- [2-methyl-1- (1 H-1, 2,4-triazol-1-yl) propyl] -2 (1 H) -quinoxalinone (compound No. 20 in the present application), 3-ethyl-6- [1- (1H-imidazol-1-yl) -2-methylpropyl] -2 (1H) -quinoxalinone (compound No. 21 in the present application), 6- [ 2-methyl-1- (1H-1, 2,4-triazol-1-yl) propyl] -3- (2-thienyl) -2 (1 / - /) - quinoxalinone (compound No. 22 in the present application ), 6- [2-methy1- (1H-1, 2,4-triazol-1-yl) propyl] -3- (thienyl) -2 (1 H) -quinoxalinone (compound No. 23 in the present application), 6- [1- (1R7-imidazol-1-yl) -2-methylpropyl] -3- (3-thienyl) -2 (1 H) -quinoxalinone (compound No. 24 in the present application ) and 6- [1- (1H-imidazol-1-yl) pentyl] -3-m (compound No. 25 in the present application). Unexpectedly, it has been found that the compounds of the present invention exhibit PARP inhibitory activity. A first group of compounds of interest consists of the compounds of formula (I) wherein one or more of the following restrictions apply: a) n is O or 1; b) X is N or CR5 wherein R5 is hydrogen; c) R3 is a radical selected from (a-1), (a-2) or (a-3), or is a group of formula (b-1), i.e., -Z-; d) s is 0, 1 or 2; e) R6 is -CHO, C-? -6 alkyl, piperidinyl-C? -6 alkyl, arylcarbonylpiperidinyl-C1-6 alkyl or arylalkyl (C? -6) - (C? _) alkyl-aminoalkyl C? -6; f) R8 is C6 alkyl; g) when R3 is a group of formula (b-1), then Z is a heterocyclic ring system selected from (c-2) or (c-4); and h) each R 10 is independently hydrogen, d-β alkyl or (C 6 -6) alkyloxy of C 6 -6. A second group of compounds of interest consists of the compounds of formula (I) wherein one or more of the following restrictions apply: a) n is 0; b) X is N or CR5, wherein R5 is hydrogen; c) R1 is C1-6 alkyl; d) R2 is hydrogen or hydroxy, or together with R4 can form = O; e) R3 is a radical selected from (a-1) or (a-2); f) s is 0 or 1; g) R6 is -CHO or C? -6 alkyl; and h) R4 is hydrogen, C-? 6 alkyl or A third group of compounds of interest consists of the compounds of formula (I), the first group of compounds of interest or the second group of compounds of interest, wherein Z is a heterocyclic ring system different from the heterocyclic ring system of formula (c-2) or (c-4). A group of preferred compounds consists of the compounds of formula (I) wherein n is 0 or 1; X is N or CR5, wherein R5 is hydrogen; R3 is a radical selected from (a-1), (a-2) or (a-3), or is a group of formula (b-1), that is, -Z-; s is 0, 1 or 2; R6 is -CHO, C? -6 alkyl, piperidinyl-C-? -6 alkyl, arylcarbonyl-pyridinyl-C? -6 alkyl or arylalkyl (C? -6) - (C? C1-6; R8 is Ci-β alkyl, 'when R3 is a group of formula (b-1), then Z is a heterocyclic ring system selected from (c-2) or (c-4); and each R 10 is independently hydrogen, C 1-6 alkyl or aicyloxy (C? -6) -alkylamino of C-t-β. An additional group of preferred compounds consists of the compounds of formula (I) wherein n is 0; X is N or CR5, wherein R5 is hydrogen; R1 is C-? -6 alkyl; R2 is hydrogen or hydroxy, or together with R4 can form = 0; R3 is a radical selected from (a-1) or (a-2); s is 0 or 1; R6 is -CHO or C1-6 alkyl; and R 4 is hydrogen, C 1-6 alkyl or A further group of preferred compounds consists of the compounds of formula (I), the group of preferred compounds or the additional group of preferred compounds, wherein Z is a heterocyclic ring system different from the heterocyclic ring system of formula (c-2) ) or (c- 4). The most preferred compounds are compound No.1, compound No.5, compound No.7, compound No. 3 and compound No. 17.

The compounds of formula (I) can be prepared according to the general methods described in EP 371564. Several of these methods will be described later in greater detail. In the examples, other methods for obtaining final compounds of formula (I) are described. The compounds of formula (I) wherein R2 is hydrogen and R3 is -NR7-CHO, wherein R7 is hydrogen or methyl, referred to herein as the compounds of formula (lb), can be prepared starting from the compounds of formula (I) ) wherein R2 together with R3 form = O, referred to herein as the compounds of formula (Ia), in the presence of formamide or methylformamide, indicated herein as intermediates of formula (II), and formic acid.

The compounds of formula (I) wherein R3 is hydroxy, referred to herein as the compounds of formula (Ic), can be prepared by converting the ketone portion of the compounds of formula (Ia) to a hydroxy group, with an appropriate reductant, by for example sodium borohydride, in a suitable solvent, for example methanol and tetrahydrofuran.

The compounds of formula (Ia) can be prepared by converting the compounds of formula (Ic) wherein R 2 is hydrogen, referred to herein as the compounds of formula (I-1), in the presence of a suitable oxidant, such as chromium trioxide, and an acid such as sulfuric acid, in a suitable solvent, such as 2-propanone.

Intermediates of formula (IV) wherein W is a suitable leaving group, such as for example chlorine, bromine, methanesulfonyloxy or benzenesulfonyloxy, can be prepared from the compounds of formula (I-1) by treating said compounds with a suitable reagent, Examples are methanesulfonyl chloride or benzenesulfonyl chloride, or a halogenation reagent, such as for example POCI3 or SOCI2.

The compounds of formula (I) defined as compounds of formula (I) wherein R is as defined in R6 and Rc is as defined in R7, or Rb and Rc together with the nitrogen to which they are attached form a ring system Suitable heterocyclic as defined in Z, referred to herein as the compounds of formula (Ih), can be prepared by reacting an intermediate of formula (IV) with an intermediate of formula (V). The reaction can be carried out in an inert reaction solvent, such as dimethylformamide or acetonitrile, and optionally in the presence of a suitable base, such as for example sodium carbonate, potassium carbonate or triethylamine.

The compounds of formula (I) can also be converted to one another by means of known reactions or transformations of functional groups. Several of these transformations have already been described above. Other examples are the hydrolysis of carboxylic esters to the corresponding carboxylic acid or alcohol; hydrolysis of amides to the corresponding carboxylic acids or amines; hydrolysis of nitriles to the corresponding amides; the amino groups on imidazole or phenyl can be replaced with a hydrogen by known diazotization reactions, and subsequent replacement of the diazo group with hydrogen; the alcohols can be converted into esters and ethers; the primary amines can be converted to secondary or tertiary amines; the double bonds can be hydrogenated to give the corresponding single bond; an iodo radical on a phenyl group can be converted to an ester group by the insertion of carbon monoxide in the presence of a suitable palladium catalyst. Therefore, the compounds of the formulas (I), (I-a), (l-b), (l-c), (lc-1), (lh), (li), (lj) and (lk) can optionally be the subject of one or more of the following conversions in any desired order: (i) converting a compound of formula (I) in a compound of formula (I) different; (ii) converting a compound of formula (I) to its corresponding salt or N-oxide acceptable; (iii) converting a pharmaceutically acceptable salt or N-oxide of a compound of formula (I) into the parent compound of formula (I); (iv) preparing an isomeric stereochemical form of a compound of formula (I) or a pharmaceutically acceptable salt or N-oxide thereof. Intermediates of formula (VII) in which Rd and Re are appropriate radicals or form, together with the carbon to which they are attached, an appropriate heterocyclic ring system as defined in Z, can be prepared by hydrolyzing the intermediates of formula (VI). ) wherein R3 is a group of formula (b-1) or a radical of formula (a-1) wherein s is different from 0, referred to herein as R9, according to known methods, for example by stirring the intermediate ( VI) in an aqueous acidic solution in the presence of an inert reaction solvent, for example tetrahydrofuran. A suitable acid is, for example, hydrochloric acid. evo < VÍÍ > The compounds of formula (I) wherein R2 is hydrogen and R9 is as defined above, referred to herein as the compounds of formula (Ik), can be prepared starting from the intermediates of formula (VII) by means of a selective hydrogenation of said intermediate with a suitable reducing agent, such as for example with a noble metal catalyst, such as platinum on carbon, palladium on carbon and the like, and a suitable reductant such as hydrogen, in a suitable solvent such as methanol.

The compounds of formula (I) can be prepared by hydrolyzing the Intermediates of formula (VIII) according to known methods, subjecting the intermediates of formula (VIII) to the appropriate reagents, such as tin chloride, acetic acid and hydrochloric acid, in the presence of an inert reaction solvent, for example tetrahydrofuran.

(VED (!) The compounds of formula (I) can be prepared starting from N-oxides of formula (IX), by converting the intermediates of formula (IX) in the presence of a suitable reagent, such as sodium carbonate or acetic anhydride, and when appropriate in a solvent such as dichloromethane. (ix) (D The compounds of formula (I) wherein X is CH, referred to herein as the compounds of formula (Ij), can also be obtained by cyclization of an intermediate of formula (X). intermediates of formula (X) can be made according to known cyclization procedures Preferably the reaction is carried out in the presence of a suitable Lewis acid, for example aluminum chloride, either neat or in a suitable solvent, such as example an aromatic hydrocarbon, for example, benzene, chlorobenzene, methylbenzene and the like, halogenated hydrocarbons, for example, trichloromethane, tetrachloromethane and the like, an ether, for example, tetrahydrofuran, 1,4-dioxane and the like, or mixtures of such solvents. The reaction can be accelerated using slightly elevated temperatures, preferably between 70 ° C-100 ° C, and stirring.

Compounds of formula (I) wherein X is N, referred to herein as the compounds of formula (1-), can be obtained by condensing an appropriate ortho-benzenediamine of formula (XI) with an ester of formula (XII) wherein Rh is C6 alkyl. The condensation of the substituted ortho-diamine of formula (XI) and the ester of formula (XII) can be carried out in the presence of a carboxylic acid, for example acetic acid and the like; a mineral acid, such as for example hydrochloric acid, sulfuric acid or a sulfonic acid, such as for example methanesulfonyl acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid and the like. It may be appropriate to use slightly elevated temperatures to accelerate the reaction and even, in some cases, the reaction may be carried out at the reflux temperature of the reaction mixture. The water released during condensation can be removed from the mixture by distillation, azeotropic distillation, and similar methods.

The intermediates of formula (XI) can be prepared by a nitro to amino reduction reaction, starting from an intermediate of formula (XIII) in the presence of a metal catalyst, such as Raney nickel, and a suitable reductant such as hydrogen, in a suitable solvent such as methanol.

(Xyl?) ^^ Intermediates of formula (XIII) can be prepared by hydrolysis of the intermediates of formula (XIV) according to known methods, such as agitation of intermediate (XIV) in an aqueous solution of acid in the presence of of an inert reaction solvent, for example tetrahydrofuran. A suitable acid is, for example, hydrochloric acid. (rv) { xrp > The intermediates of formula (X) can be conveniently prepared by reacting an aniline of formula (XV) with a halogenide of formula (XVI), in the presence of a base such as pyridine, in a suitable solvent such as dichloromethane.

(XV) w The intermediates of formula (VIII) wherein n is 0, R2 is hydrogen or hydroxy and when R2 is hydrogen and then R3 is hydroxy, referred to herein as the intermediates of formula (Vlll-a), they can be prepared by treating an intermediate of formula (XVII) wherein W is halogen, with an organolithium reagent, such as for example n-butyl lithium, in an inert reaction solvent, for example tetrahydrofuran, and subsequently reacting said intermediate with an intermediate of formula (XVIII) wherein R 'is hydrogen or a radical as defined in R3. (xvp íxvim ÍVpi-a) The present invention also relates to a compound of formula (I) as defined above, for use as a medicine. The compounds of the present invention have PARP inhibition properties as can be seen in the experimental part below. The present invention also contemplates the use of the compounds in the preparation of a medicament for the treatment of any of the diseases and disorders described herein in an animal, wherein said compounds are the compounds of formula (I), the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein: "n is 0, 1 or 2; X is N or CR 5, wherein R 5 is hydrogen, or together with R 1 may be forming a bivalent radical of formula -CH = CH-CH = CH-; R 1 is C 1-6 alkyl or thienyl; R is hydrogen or hydroxy, or together with R or R4 can form = O; R3 is a radical selected from: - (CH2) S-NR6R7 (a-1), -OH (a-2), -O-R8 (a-3), -S-R9 (a-4), or - C = N (a-5), where: s is O, 1, 2 or 3; R6 is -CHO, C1-6alkyl, hydroxyC1.6alkyl) alkylC-id) -carbonyl, di (C1-6alkyl) -amino-Ci-βalkyl, alkyloxy (C-? 6) -alkyl of C-¡. 6, alkyl (C? -6) -carbonylamino-C? -6 alkyl, piperidinyl-alkyl (C? -6) -aminocarbonyl, piperidinyl, piperidinyl-C1-6alkyl, piperidinyl-alky (C? 6) aminocarbonyl, C?-6alkyloxy, thienyl-C?-6alkyl, pyrrolyl-Ci-βalkyl, aryl-C (-6-alkylpiperidinyl, arylcarbonyl-C?-6alkyl, arylcarbonylpiperidinyl -alkyl of C? -6, haloindozolylpiperidinyl-C? -6 alkyl, or aryl-alkyl (C? -6) - (C? .6 alkyl) -amino-C1-6 alkyl; R7 is hydrogen or C-i-β alkyl; R8 is Ci-β alkyl, (C6-6) alkylcarbonyl or di (Ci-e) alkyl-amino-C1-6alkyl; and R9 is di (C6-alkyl) -amino-C6-alkyl; or R3 is a group of formula: -Z- (b-1), wherein: Z is a heterocyclic ring system selected from: (c-3) (c-4) (c- 1) wherein each R10 is, independently, hydrogen, C-? -6 alkyl, aminocarbonyl, hydroxy, alcaotüil (C.g (C6-6) -alkyloxy-C6-6alkyl, (C6-6) alkyloxy-C1-6alkylamino, aryl-C6alkyl, di (phenyl-C2-6alkenyl), piperidinyl -C1-6alkyl, C3-cycloalkyl, or (C3-10) cycloalkyl-C6-alkyl, aryloxy (hydroxy) -C6-alkyl, haloindazolyl, aryl-d-β alkyl, C2-6 aryl-alkenyl, morpholino, (C1-6) alkyl-imidazolyl, or pyridinyl-alkyl (C6-6) amino; R 4 is hydrogen, C 6 alkyl, furanyl, pyridinyl, C 1-6 alkylaryl or aryl is phenyl or phenyl substituted by halogen, C? -6 alkyl or C? -6 alkyloxy. In view of their PARP-binding properties, the compounds of the present invention can be used as reference compounds or tracer compounds, in which case one of the atoms of the molecule can be replaced, for example, with a radioactive isotope. To prepare the pharmaceutical compositions of this invention, an effective amount of a particular compound, in the form of base or acid addition salt, is combined as the active ingredient in intimate admixture with a pharmaceutically acceptable carrier; said vehicle may have a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are conveniently in a suitable unit dosage form, preferably for oral, rectal, percutaneous administration, or by parenteral injection. For example, to prepare compositions in oral dosage forms, any of the usual pharmaceutical media, such as for example water, glycols, oils, alcohols and the like, can be used for preparations - oral liquids such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like, for powders, pills, capsules and tablets.

Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the vehicle will usually comprise sterile water, at least for the most part, although other ingredients may be included, for example to aid in dissolution. For example, injectable solutions may be prepared in which the vehicle comprises saline solution, glucose solution or a mixture of both. Injectable suspensions may also be prepared, in which case suitable liquid carriers, suspending agents and the like may be employed. In compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent, or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions., said additives do not cause a significant harmful effect on the skin. Said additives may facilitate administration to the skin or may be helpful in preparing the desired compositions. These compositions can be administered in various ways, for example as a transdermal patch, as a preparation for spot application, as an ointment. It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form to facilitate administration and uniformity of dosage. The unit dosage form, as used in the specification and claims herein, refers to physically separate units suitable as unit doses, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect, in association with the pharmaceutical vehicle required. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, tablespoons, teaspoons and the like, and segregated multiples thereof. The compounds of the present invention can treat or prevent tissue damage that results from cell damage or death due to necrosis or apoptosis.; can alleviate damage to neural or cardiovascular tissue, including that which occurs after focal ischemia, myocardial infarction and reperfusion injury; can treat various diseases and conditions caused or exacerbated by PARP activity; they can prolong or increase the life span or the proliferative capacity of the cells; can alter the genetic expression of senescent cells; they can radiosensitize or chemosensitize the cells. Generally, the inhibition of PARP activity prevents the cells from losing energy, preventing, in the case of neural cells, the irreversible depolarization of neurons, and therefore provides neuroprotection. For the above reasons, the present invention, moreover, relates to a method of administering a therapeutically effective amount of the above-identified compounds, in an amount sufficient to inhibit PARP activity, to treat or prevent tissue damage that is originates from damage or cell death due to necrosis or apoptosis; to affect a neuronal activity not mediated by NMDA toxicity; to affect a neuronal activity mediated by de'NMDA toxicity; to treat neural tissue damage that originates from ischemia and reperfusion injury, neurological disorders and neurodegenerative diseases; to prevent or treat vascular attack; to treat or prevent cardiovascular disorders; to treat other conditions or disorders such as "muscle degeneration related to aging, AIDS and other diseases of immune senescence, inflammation, gout, arthritis, atherosclerosis, cachexia, cancer, skeletal muscle degenerative diseases that include replicative senescence, diabetes, head trauma, inflammatory bowel disorders (such as colitis and Crohn's disease), muscular dystrophy, osteoarthritis, osteoporosis, chronic or acute pain (such as neuropathic pain), renal failure, retinal ischemia, septic shock (such as endotoxic shock) ), and aging of the skin, to prolong the life and proliferative capacity of cells, to alter the genetic expression of senescent cells, to chemosensitize or radiosensitize tumor cells (hypoxic) The present invention also refers to the treatment of diseases and conditions in an animal, comprising administering to said animal a Therapeutically effective amount of the compounds previously identified. In particular, the present invention relates to a method of treating, preventing or inhibiting a neurological disorder in an animal, comprising administering to said animal a therapeutically effective amount of the compounds identified above. The neurological disorder is selected from the group consisting of peripheral neuropathy caused by physical injury or pathological condition, traumatic brain injury, physical damage to the spinal cord, brain attack associated with brain damage, focal ischemia, global ischemia, reperfusion injury , demyelinating disease and neurological disorder related to neurodegeneration. The present invention also contemplates the use of the compounds of formula (i) to inhibit the activity of PARP, to treat, prevent, or inhibit tissue damage that results from cell damage or death due to necrosis or apoptosis, to treat, prevent or inhibit a neurological disorder in an animal. The term "prevent neurodegeneration" includes the ability to prevent neurodegeneration in newly diagnosed patients with a neurodegenerative disease, or at risk of developing a new degenerative disease, and to prevent the advance of neurodegeneration in patients who already suffer from the symptoms of a neurodegenerative disease. The term "treatment", as used herein, covers any treatment of a disease or condition in an animal, particularly a "human being, and includes: (i) preventing the occurrence of a disease or condition in a subject that may be predisposed to the disease or condition, but has not yet been diagnosed as having; (ii) inhibit the disease or condition, that is, stop its development; (iii) alleviating the disease or condition, that is, causing the regression of the disease or condition. The term "radiosensitizer", as used herein, is defined as a molecule, preferably a low molecular weight molecule, administered to animals in therapeutically effective amounts to increase the sensitivity of cells to ionizing radiation, or to promote treatment of diseases that are treatable with ionizing radiation. Diseases that are treatable with ionizing radiation include neoplastic diseases, benign and malignant tumors, and cancer cells. The present invention also contemplates the treatment of other diseases not indicated herein with ionizing radiation. The term "chemosensitizer", as used herein, is defined as a molecule, preferably a "low molecular weight" molecule, administered to animals in therapeutically effective amounts to increase the sensitivity of the cells to chemotherapy, or to promote the treatment of diseases that are treatable with chemotherapeutic agents Diseases that are treatable with chemotherapy include neoplastic diseases, benign and malignant tumors, and cancer cells.The present invention also contemplates the treatment of other diseases not indicated herein with chemotherapy. The compositions and methods of the present invention are particularly useful for treating or preventing tissue damage that results from cell death or damage due to necrosis or apoptosis The compounds of the present invention may be "anticancer agents"; "agents against the growth of tumor cells "and" antineoplastic agents ". For example, the methods of the invention are useful for the treatment of cancer and for chemosensitizing or radiosensitizing tumor cells in cancer, such as ACTH-producing tumors, acute lymphocytic leukemia, acute lymphocytic leukemia, adrenal cortex cancer, bladder cancer, brain cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia, chronic myelocytic leukemia, colorectal cancer, cutaneous T-cell lymphoma, endometrial cancer, cancer of the esophagus, Ewing's sarcoma, gallbladder cancer , hairy cell leukemia, cancer of the head and neck, Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer, liver cancer, lung cancer (small cell 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, prostate cancer, pancreatic cancer, cancer of the penis, retinoblastoma, skin cancer, soft tissue sarcoma, squamous cell carcinomas, stomach cancer, testicular cancer, thyroid cancer, trophoblastic neoplasms, uterine cancer, vaginal cancer, vulvar cancer and Wilm's tumor. Therefore, the compounds of the present invention can be used as "radiosensitizers" or "chemosensitizers".

It is known that radiosensitizers increase the sensitivity of cancer cells to the toxic effects of ionizing radiation. Several mechanisms have been suggested in the literature for the mode of action of radiosensitizers that include: radiosensitizers of hypoxic cells (for example 2-nitroimidazole compounds and benzotriazine dioxide compounds), mimic oxygen or alternatively behave as hypochlorite agents under hypoxia; the non-hypoxic cell radiosensitizers (for example the halogenated pyrimidines), can be analogs of DNA bases and are preferably incorporated into the DNA of the cancer cells, and thus promote the breakdown of the radiation-induced DNA molecules, or prevent the normal mechanisms of DNA repair; and hypotheses have been made of other possible mechanisms of action of radiosensitizers in the treatment of diseases. Currently many cancer treatment protocols employ radiosensitizers in conjunction with X-ray radiation. Examples of X-ray-activated radiosensitizers include, without limitation, the following: metronidazole, misonidazole, desmethylmisonidazole, pimonidazole, etanidazole, nimorazole, mitomycin C, RSU 1069 , SR 4233, E09, RB 6145, nicotinamide, 5-bromodeoxyuridine (BUdR), 5-iododeoxyuridine (lUdR), bromodeoxycytidine, fluorodeoxyuridine (FudR), hydroxyurea, cisplatin, and therapeutically effective analogs and derivatives thereof. Photodynamic therapy (PDT) of cancer uses visible light as the radiation activator of the sensitizing agent. Examples of photodynamic radiosensitizers include the following, without limitation: hematoporphyrin derivatives, photofrina, benzoporphyrin derivatives, tin ethioporphyrin, pheoborbide, bacteriochlorophyll a, naphthalocyanines, phthalocyanines, zinc phthalocyanine and therapeutically effective analogs and derivatives thereof. The radiosensitizers can be administered in conjunction with a therapeutically effective amount of one or more compounds, including without limitation: compounds that promote the incorporation of the radiosensitizers into the target cells; compounds that control the flow of therapeutic agents, nutrients or oxygen to the target cells; chemotherapeutic agents that act on the tumor with or without additional radiation; or "other therapeutically effective compounds for the treatment of cancer or other disease." Examples of additional therapeutic agents that may be used in conjunction with radiosensitizers include, without limitation: 5-fluorouracil, leucovorin, 5'-amino-5'-deoxythymidine , oxygen, "carbogen, erythrocyte transfusions, perfluorocarbons (for example Fluosol 10 DA), 2,3-DPG, BW12C, calcium channel blockers, pentoxifylline, antiangiogenesis compounds, hydralazine and LBSO. Examples of chemotherapeutic agents that may be used in conjunction with radiosensitizers include, without limitation: adriamycin, camptothecin, carboplatin, cisplatin, daunorubicin, docetaxei, interferon (alpha, beta, gamma), interleukin 2, irinotecan, paclitaxel, topotecan, and therapeutically effective analogs and derivatives thereof.

The chemosensitizers can be administered in conjunction with a therapeutically effective amount of one or more other compounds, including, without limitation: compounds that promote the incorporation of chemosensitizers into the target cells; compounds that control the flow of therapeutic agents, nutrients, or oxygen to the target cells; chemotherapeutic agents that act on the tumor, or other therapeutically effective compounds to treat cancer or other diseases. Examples of additional therapeutic agents that can be used in conjunction with chemosensitizers include, without limitation: methylation agents, topoisomerase 1 inhibitors, other chemotherapeutic agents such as cispiatin and bleomycin. The compounds of formula (I) can also be used to detect or identify PARP, and more particularly the PARP 1 receptor. For this purpose, the compounds of formula (I) can be labeled. Said label can be selected from the group consisting of a radioisotope, spin tag, antigen tag, enzyme-labeled fluorescent group, or a chemiluminescent group. Those skilled in the art can easily determine the effective amount based on the test results presented below. In general, it is contemplated that an effective amount would be from 0.01 mg / kg to 100 mg / kg of body weight; in particular from 0.05 mg / kg to 10 mg / kg of body weight. It may be appropriate to administer the required dose as 2, 3, 4 or more sub-doses at appropriate intervals during the day. Said sub-doses can be formulated as unit dosage forms, for example containing from 0.5 to 500 mg, in particular from 1 mg to 200 mg of the active ingredient per unit dosage form. The following examples illustrate the present invention.

Experimental part Hereinafter, "BuLi" defines butyl lithium, "DCM" is defined as dichloromethane, "DIPE" is defined as diisopropyl ether, "DMF" is defined as? /,? / - dimethylformamide, "EtOAc" is defined as ethyl acetate, "EtOH" is defined as ethanol, "MEK" is defined as methyl ethyl ketone, "MeOH" is defined as methanol, and "THF" is defined as tetrahydrofuran.

A) Preparation of intermediate compounds EXAMPLE A1 a) Preparation of the intermediary 1 A mixture of 1- (4-amino-3-nitrophenyl) -2-methyl-1-propanone (0.0144 mol) in formic acid (4.93 ml) and formamide (18.2 ml) was stirred at 160 ° C for 15 hours; it was then cooled to room temperature, poured into ice water, basified with a concentrated solution of ammonium hydroxide and extracted with EtOAc. The organic layer was separated, dried (MgSO 4), filtered, and the solvent was evaporated to dryness, yielding 4.8 g of intermediate 1. b) Preparation of the intermediary 2 A mixture of intermediate 1 (0.0144 mol) in MeOH (50 ml) was hydrogenated under a pressure of 3 bar for one hour with Raney nickel (3.4 g) as a catalyst. After incorporation of H2 (3 equivalents), the catalyst was filtered through celite, washed with MeOH and the filtrate was evaporated to dryness. The product was used without further purification, yielding 4.7g of intermediate 2.

EXAMPLE A2 Preparation of intermediaries 3 and 4 Intermediary 3 Intermediary 4 Aluminum chloride (0.6928 mol) was added in portions to a solution of chloroacetyl chloride (0.5196 mol) in DCM (50.2 ml), keeping the temperature below 30 ° C. 3-Ethyl-2 (1H) -quinolinone (0.1732 mol) was added maintaining the temperature below 30 ° C. The mixture was stirred and refluxed for 15 hours; it was cooled and emptied in ice water. The precipitate was separated by filtration, washed with water and taken up in DCM. The organic solution was stirred and filtered. The precipitate was dried, yielding 33.5g of intermediate 3. The filtrate was extracted. The organic layer was separated, dried (MgSO) and filtered; the solvent was evaporated to dryness, yielding 20.46g of intermediate 4.

EXAMPLE A3 a) Preparation of the intermediary 5"XXX A mixture of 6-bromo-2-chloro-3-methyl-quinoline (0.04483 mol) and CH3ONa (0.224 mol) in MeOH (200 ml) was stirred at 70 ° C for 36 hours. The mixture was cooled, emptied on ice and EtOAc was added, and the mixture was extracted with EtOAc. The organic layer was washed with water, dried (MgSO), separated by filtration and evaporated, yielding 11 g (97%) of Intermediate 5. b) Preparation of the intermediary 6 To a mixture of intermediate 5 (0.0476 mol) in THF (200 ml) BuLi 1.6M in hexane (0.0619 mol) was added dropwise at -60 ° C under a flow of N2. The mixture was stirred at -60 ° C for 1 hour. A mixture of 3- (dimethylamino) -1- (2-furanyl) -1-propanone (0.0571 mol) in THF (100 ml) was added dropwise at -60 ° C. The mixture was stirred at -60 ° C for 2 hours and then at -40 ° C for 1 hour. The mixture was poured into a saturated solution of ammonium chloride and extracted with EtOAc. The organic layer was separated, dried (MgSO4) and filtered, and the solvent was evaporated. The product was used without further purification, producing 16.2g of intermediate 6. c) Preparation of the intermediary 7 A mixture of intermediate 6 (0.0476 mol) in 3N hydrochloric acid (254 ml) and THF (128 ml) was stirred and refluxed for 6 hours. The mixture was emptied on ice, basified with a concentrated solution of ammonium hydroxide and extracted with EtOAc. The organic layer was separated, dried (MgSO4) and filtered, and the solvent was evaporated. The residue was purified by column chromatography on silica gel (15-40μm) (eluent: DCM / MeOH / NH 4 OH 95/5 / 0.2). The pure fractions were collected and the solvent was evaporated, yielding 4g (27%) of the intermediate 7.

EXAMPLE A4 Preparing the intermediary 8 To a mixture of 6-bromo-3-ethyl-2-methoxy-quinoline (0.0996 mol) in THF (265 ml) was added dropwise nBuLi 1.6M in hexane (0.129 mol) at -60 ° C and under a N2 flow. The mixture was stirred at -60 ° C for 1 hour. A mixture of 2-ethyl-butanal (0.119 ml) in THF (100 ml) was added dropwise at -60 ° C. The mixture was stirred at -60 ° C for 2 hours, then at -40 ° C for 1 hour.; it was emptied into a saturated solution of ammonium chloride and extracted with EtOAc. The organic layer was separated, dried (MgSO4) and filtered, and the solvent was evaporated. The product was used without further purification, producing 28.62g of intermediate 8.

EXAMPLE A5 a) Preparing the intermediary 9 To a slurry of Mg filings (0.21 mol) in diethyl ether (125 ml) was added dropwise a solution of (2-bromoethyl) benzene (0.174 mol) in diethyl ether (125 ml) at 0 ° C, and the The mixture was stirred at 0 ° C for 1 hour. A solution of 3-methyl-6-quinolinecarboxaldehyde (0.116 mol) in THF (200 ml) was added dropwise at 0 ° C, and the mixture was stirred at room temperature for 2 hours. The mixture was poured into ice water, filtered through celite and the product was extracted with EtOAc. The organic layer was washed with water, dried (MgSO), filtered off and evaporated. The residue was crystallized from EtOAc / diethyl ether, yielding 19 g (59%) of intermediate 9. b) Preparation of the intermediary 10 To a solution of intermediate 9 (0.069 mol) in DCM (300 ml) and tris [2- (2-methoxyethoxy) ethyl] amine (2 ml), potassium permanganate (19 g) was added dropwise at 5 ° C and under N 2. , and the mixture was stirred at room temperature overnight. The mixture was filtered through celite and the filtrate was evaporated, yielding 17g (90%) of intermediate 10. c) Preparation of the intermediary 11 To a solution of intermediate 10 (0.062 mol) in DCM (200 ml) was added a solution of 3-chloro-benzenecarboperoxioc acid (0.123 mol) in DCM (200 ml), at 5 ° C and under N2; the mixture was stirred at 5 ° C for 1 hour and then at room temperature for 3 hours. 10% aqueous potassium carbonate was added and the product was extracted with DCM. The organic layer was washed with water, dried (MgSO4), filtered off and evaporated. The product was used without further purification, producing 18g (100%) of the intermediate 11. d) Preparation of the intermediary 12 To a solution of intermediate 11 (0.062 mol) in DCM (250 ml) was added 10% potassium carbonate (250 ml) at room temperature, and the mixture was stirred for 10 minutes. Tosyl chloride (0.093 mol) was added portionwise and the mixture was stirred at room temperature for 2 hours. The precipitate was separated by filtration, washed with water and dried. The residue (10.1g) was recrystallized from 2-propanone, yielding 2.8g (72%) of intermediate 12.

B. Preparation of the final compounds EXAMPLE B1 Preparation of the final compound 1 A mixture of intermediate 2 (0.011 mol) and ethyl 2-oxobutanoate (0.022 mol) in EtOH (40 ml) was stirred at 60 ° C for 6 hours, and then cooled to room temperature. The solvent was evaporated. The residue was taken in a saturated solution of NaHCO3. The mixture was extracted with DCM. The organic layer was separated, dried (MgSO4) and filtered, and the solvent was evaporated to dryness. The residue was purified by column chromatography on silica gel (15-40 μm) (eluent: DCM / MeOH / NH 4 OH 99/1 / 0.1 and 85/15 / 0.1). The pure fractions were collected and the solvent was evaporated. The residue (1.9 g) was again purified by column chromatography on silica gel (15-40 μm) (eluent: cyclohexane / 2-propanol / NH 4 OH 88/12/1). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from DI PE. The precipitate was separated by filtration and dried, yielding 0.33 g (11%) of compound 1, melting point 204 ° C.

EXAMPLE B2 Preparation of final compound 2 To a solution of / V- [4- [1- (1 / - imidazol-1-yl) -2-methylpropyl] phenylj-2-methyl-3-phenyl-2-propenamide (0.026 mol) in chlorobenzene (60ml aluminum chloride (0.234 mol) was added in portions, and the mixture was stirred at 100 ° C for 3 hours. The mixture was poured into ice water, basified with NH 4 OH and extracted with DCM. The mixture was filtered through celite and the filtrate was decanted. The organic layer was dried (MgSO), filtered off and evaporated to dryness. The residue was purified by column chromatography on silica gel (35-70 μm) (eluent: DCM / MeOH / NH 4 OH 95/5 / 0.1). The pure fractions were collected and the product was evaporated. The residue (4g) was crystallized from MEK, yielding 2.12g (29%) of compound 2, melting at 211.4 ° C.

EXAMPLE B3 Preparation of the final compound 3 To a suspension of potassium carbonate (0.3603 mol) in DMF (300 ml), dimethylamine hydrochloride (0.3 mol) was added portionwise at room temperature and under a flow of N2. The mixture was stirred 30 minutes. A mixture of intermediate 3 (0.06 mol) and intermediate 4 (0.06 mol) was carefully added. The mixture was stirred at room temperature for 30 minutes. Ice water was added. The precipitate was separated by filtration, washed with water and the filtrate was extracted with DCM. The organic layer was separated, dried (MgSO4) and filtered, and the solvent was evaporated to dryness. The residue (16.6g) was purified by column chromatography on silica gel (20-45 μm) (eluent: DCM / MeOH / NH 4 OH 95/5 / 0.2). The pure fractions were collected and the solvent was evaporated. The residue (4.9g) was crystallized from 2-propanone and MeOH. The precipitate was separated by filtration and dried, yielding 1.2g of compound 3, melting point 180 ° C.

EXAMPLE B4 Preparation of the final compound 4 A mixture of intermediate 7 (0.0113 mol) in MeOH (60 ml) was hydrogenated at 40 ° C, under a pressure of 4.8 bar for 6 hours, with 10% Pd / C (0.35 g) as catalyst. After incorporation of H2 (1 eq), the catalyst was filtered over celite and the filtrate was evaporated. The residue was taken up in water and a concentrated solution of ammonium hydroxide, and extracted with DCM. The organic layer was separated, dried (MgSO4) and filtered, and the solvent was evaporated. The residue was purified by column chromatography on silica gel (15-40 μm) (eluent: DCM / MeOH / NH 4 OH 95/5 / 0.3 and 93/7 / 0.5). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from 2-propanone and diethyl ether. The precipitate was separated by filtration and dried, yielding 0.69g (20%) of compound 4.

EXAMPLE B5 Preparation of the final compound 5 A mixture of intermediate 8 (0.0996 mol) in hydrochloric acid 3N (426 mL) and THF (274 mL) was stirred at 70 ° C overnight; it was then emptied on ice, basified with a concentrated solution of NH OH and extracted with EtOAc. The organic layer was separated, dried (MgSO4) and filtered, and the solvent was evaporated. The residue was crystallized from DCM. The precipitate was separated by filtration and dried, yielding 15.21g (56%) of compound 5.

EXAMPLE B6 Preparation of the final compound 6 A mixture of intermediate 12 (0.012 mol) in formamide (61.8 ml) and formic acid (30 ml) was stirred and refluxed for 36 hours. The mixture was cooled to room temperature, emptied into ice water and separated by filtration. The precipitate was washed with water, 2-propanone and diethyl ether. The precipitate was dried and recrystallized from MeOH / THF, yielding 1.74g (40%) of compound 6, melting point 221.3 ° O EXAMPLE B7 Preparation of the final compound 7 To a solution of compound 3 (0.0116 mol) in MeOH (50 ml) was added sodium hydroborate (0.0151 mol) at 0 ° C and under a flow of N2. The mixture was stirred 1 hour and was poured into water. The organic solvent was evaporated. The aqueous concentrate was taken in DCM and water, and the mixture was extracted. The organic layer was separated, dried (MgSO4) and filtered, and the solvent was evaporated to dryness. The residue was crystallized from 2-propanone and MeOH. The precipitate was separated by filtration, washed with diethyl ether and dried, yielding 1.2g of compound 7, melting point 131 ° C. Table F1 indicates the compounds that were prepared according to one of the above examples. The following abbreviations were used in the tables.

F1 frame Table F1 (Continued) Pharmacological example In vitro scintillation proximity test (SPA) for the inhibitory activity of PARP-1 The compounds of the present invention were analyzed with an in vitro test based on SPA technology (property of Amersham Pharmacia Biotech). In principle, the test is based on well-established SPA technology for the detection of poly (ADP-ribosylation) of biotinylated target proteins, that is, histones. This ribosylation is induced using the enzyme PARP-1 activated by DNA cut and [3H] -nicotinamide adenine dinucleotide ([3H] -NAD +) as an ADP-ribosyl donor. Cut DNA was prepared as an inducer of the enzymatic activity of PARP-1. For this, 25 mg of DNA (supplier: Sigma) was dissolved in 25 ml of deoxyribonuclease buffer (10 mM Tris-HC1, pH 7.4; bovine serum albumin (BSA) 0.5 mg / ml; 5 mM MgCl2.6H2O and 1 mM KCI), to which 50 μl of deoxyribonuclease solution (1 mg / ml in 0.15 M NaCl) was added. After a 90 min incubation at 37 ° C, the reaction was terminated by adding 1.45 g of NaCl, followed by further incubation at 58 ° C for 15 min. The reaction mixture was chilled on ice and dialyzed at 4 ° C for 1.5 and 2 hours respectively, against 1.5 I of 0.2 M KCI, and twice against 1.5 I of 0.01 M KCI for 1.5 and 2 hours, respectively. The mixture was divided into aliquots and stored at -20 ° C. Histones were biotinylated (1 mg / ml, type ll-A, supplier: Sigma) using the biotinylation equipment from Amersham and stored in aliquots at -20 ° C. A SPA poly (vinyltoluene) (PVT) bead supplying solution was prepared (supplier: Amersham), 100 mg / ml in PBS. A [3 H] -NAD + supply solution was made by adding 120 μl of [3 H] -NAD + (0.1 mCi / ml, supplier: NEN) to 6 ml of incubation buffer (50 mM Tris / HCl, pH 8; DTT 0.2 mM; 4 mM MgCl 2). A 4 mM NAD + solution (supplier: Roche) was prepared in incubation buffer (from a 100 mM stock solution in water stored at -20 ° C). The PARP-1 enzyme was produced using the known techniques, that is, cloning and expression of the protein starting from human liver cDNA. The information regarding the protein sequence used of the enzyme PARP-1, including literature references, can be found in the Swiss-Prot database under the main registration number P09874. Biotinylated histones and PVT-SPA beads were mixed and pre-incubated 30 min at room temperature. The enzyme PARP-1 (the concentration was dependent on the batch) was mixed with the cut DNA and the mixture was pre-incubated 30 min at 4 ° C. Equal parts of this solution of histones / PVT-SPA beads and the enzyme solution PARP-1 / DNA were mixed, and in a 96-well microtiter plate, 75 μl of this mixture was added per well, together with 1 μl. of the compound in DMSO and 25 μl of [3H] -NAD +. The final concentrations in the incubation mixture were 2 μg / ml for the biotinylated histones, 2 mg / ml for the PVT-SPA beads, 2 μg / ml for the cut DNA, and between 5 and 10 μg / ml for the PARP enzyme -1. After the mixture was incubated 15 min at room temperature, the reaction was terminated by adding 100 μl of 4 mM NAD + in incubation buffer (final concentration - 2 mM) and plates were mixed. The beads were allowed to settle for at least 15 min and the plates were transferred to a TopCountNXT ™ (Packard) for scintillation counting; the values were expressed as counts per minute (cpm). For each experiment, controls (containing PARP-1 enzyme and DMSO without compound), an incubation target (containing DMSO but not PARP-1 enzyme or compound), and samples (containing the enzyme PARP-1) were run in parallel. and the compound dissolved in DMSO). All tested compounds were dissolved and finally diluted further with DMSO. In the first case, the compounds were tested at a concentration of 10"6 M. When the compounds showed activity at 10" 6 M, a dose-response curve was made where the compounds were tested at concentrations between 10"and 5". M and 10"8 M. In each test, the blank value was subtracted from the control and sample values. The control sample represented the maximum enzymatic activity of PARP-1. For each sample, the amount of cpm was expressed as a percentage of the mean cpm value of the controls. When appropriate, the Cl50 values (concentration of the drug necessary to reduce the enzymatic activity of PARP-1 to 50% with respect to the control) were calculated, using linear interpolation between the experimental points above and below 50%. Here the effects of the test compounds are expressed as pCI5o (the value of the negative log of the Cl50 value). To validate the SPA test, 4-amino-1,8-naphthalimide was included as a reference compound. The tested compounds showed inhibitory activity at the initial test concentration of 10"6 M (see Table 2).

In vitro filtration test for the PARP-1 inhibitory activity The compounds of the present invention were tested in an in vitro filtration test by determining the activity of PARP-1 (driven in the presence of cut DNA), by its activity of poly (ADP) histone ribosylation, using [32 P] -NAD as an ADP-ribosyl donor. The radioactive ribosylated histones were precipitated with trichloroacetic acid (TCA) in 96-well filter plates and the [32 P] incorporated was measured using a scintillation counter. A mixture of histones was prepared (supply solution: 5 mg / ml in H2O), NAD + (supply solution, 100 mM in H2O), and [32 P] -NAD + in incubation buffer (Tris / HCI 50 mM, pH 8 0.2 mM DTT, 4 mM MgCl 2). A mixture of the enzyme PARP-1 (5-10 μg / ml) and cut DNA was also prepared. The cut DNA was prepared as described in the SPA in vitro for the inhibitory activity of PARP-1. 75 μl of the enzyme mixture PARP-1 / DNA together with 1 μl of the compound in DMSO and 25 μl of the histone-NAD + / [32 P] -NAD + mixture per cavity of a 96-well filter plate (0.45 μm) were added. , Millipore provider). The final concentrations in the incubation mixture were 2 μg / ml for histones, 0.1 mM for NAD +, 200 μM (0.5 μC) for [32 P] -NAD + and 2 μg / ml for cut DNA. Plates were incubated 15 min at room temperature and the reaction was terminated by adding 10 μl of 100% TCA cooled on ice, followed by the addition of 10 μl of ice-cold BSA solution (1% in H2O). The protein fraction was allowed to precipitate 10 min at 4 ° C and the plates were filtered in vacuo. The plates were subsequently washed in each well with 1 ml of 10% TCA cooled on ice, 1 ml of 5% TCA cooled on ice and 1 ml of 5% TCA at room temperature. Finally, 100 μl of scintillation solution (Microscint 40, Packard) was added to each well and the plates were transferred to a TopCountNXT ™ (supplier: Packard) for scintillation counting; the values were expressed as accounts per minute (cpm). For each experiment, controls (containing the enzyme PARP-1 and DMSO without compound), an incubation target (containing DMSO but not PARP-1 enzyme or compound), and samples (containing the PARP-enzyme) were run in parallel. 1 and the compound dissolved in DMSO). All tested compounds were dissolved and finally diluted more with DMSO. In the first case, the compounds were tested at a concentration of 10"5 M. When the compounds showed an activity at 10" 5 M, - - a dose-response curve where the compounds were tested at concentrations between 10"5 M and 10" 8 M. In each test, the blank value was subtracted from the control and sample values. The control sample represented the maximum enzymatic activity of PARP-1. For each sample, the amount of cpm was expressed as a percentage of the mean cpm value of the controls. When appropriate, the Cl50 values (concentration of the drug necessary to reduce the enzymatic activity of PARP-1 to 50% with respect to the control) were calculated, using linear interpolation between the experimental points above and below 50%. Here the effects of the test compounds are expressed as pIC50 (the value of the negative log of the CI5o value). To validate the filtration test, 4-amino-1,8-naphthalimide was included as a reference compound. The tested compounds showed inhibitory activity at the initial test concentration of 10"5 M (see Table 2).

Table 2 Table 2 (Continued) The compounds can be further evaluated in a chemo- or radiosensitization cell test, in a test that measures the inhibition of endogenous PARP-1 activity in cancer cell lines, and finally in a radiosensitization test in vivo.

Claims (12)

1. NOVELTY OF THE INVENTION CLAIMS 1. - A compound of formula (I), the? / -oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein: n is 0, 1 or 2; X is N or CR5, wherein R5 is hydrogen, or together with R1 can form a bivalent radical of formula -CH = CH-CH = CH-; R1 is C6-6 alkyl or thienyl; R2 is hydrogen or hydroxy, or together with R3 or R4 can form = O; R3 is a radical selected from: - (CH2) S-NR6R7 (a-1), -OH (a-2), -O-R8 (a-3), -S-R9 (a-4), or - C = N (a-5), where s is 0, 1, 2 or 3; R6 is -CHO, C.sub.-β alkyl, C.sub.1-6 hydroxy-alkyl, C.sub.1 -C.sub.6 -alkyl, C.sub.1 -C.sub.6 alkyl-amino-C.sub.6-alkyl , alkyloxy (C? -6) -alkyl of C? -6, alkyl (C? -6) -carbonylamino-C1-6alkyl, piperidinyl-alkyl (C? -6) -aminocarbonyl, piperidinyl, piperidinyl-alkyl of C? -6, piperidinyl-alkyi (C? 6) aminocarbonyl, C? -6-alkyloxy, thienyl-C 1-6 -alkyl, pyrrolyl-C-? -6 alkyl, aryl-alkyl (C1) -6) -piperidinyl, arylcarbonyl-C1-6alkyl, arylcarbonylpiperidinyl-C6-6alkyl, haloindozolylpiperidinyl-C6-6alkyl, or aryl-alkyl (C6-6) - (C1-6alkyl) -amino-C1-6 alkyl; R7 is hydrogen or C? -6 alkyl; R 8 is C 1-6 alkyl, C 1-6 alkylcarbonyl or di (C 1-6 alkyl) -amino-C? -6 alkyl; and R9 is di (C6-alkyl) -amino-C1-6alkyl; or R3 is a group of formula: -Z- (b-1), wherein Z is a heterocyclic ring system selected from: (c- 1) Ctr-2) (c-3) (c-4) '"' wherein each R10 is, independently, hydrogen, C6 alkyl, aminocarbonyl, hydroxy, alkanediyl < Cl.s of d-β, alkyloxy (C? -6) -alkylamino of d-6, aryl-alkyl of C ?6, di (phenyl-C2-e alkenyl), piperidinyl-C alquilo-6 alkyl, C3- [alpha] cycloalkyl, (C3- [alpha] o] cycloalkyl-C1.6alkyl, aryloxy (hydroxy) -alkyl of C [beta] -6, haloindazolyl, aryl-alkyl of d-6, aryl-alkenyl of C2-6 , morpholino, alkyl (C? 6) -imidazolyl, or pyridinyl-alkyl (C? -6) amino; R 4 is hydrogen, d-β alkyl, furanyl, pyridinyl, aryl-C 1-6 alkyl or aryl is phenyl or phenyl substituted by halogen, d-6 alkyl or Ci-alkyloxy. ß, with the proviso that: when n is 0, X is N, R2 is hydrogen, R3 is a group of formula (b-1), Z is the heterocyclic ring system (c-2) or (c-4) ), wherein said heterocyclic ring system Z is bonded to the rest of the molecule with a nitrogen atom, and R10 is hydrogen; then R4 is different from d-6 alkyl or pyridinyl.
2. 2. The compound according to claim 1, further characterized in that n is 0 or 1; X is N or CR5, wherein R5 is hydrogen; R3 is a radical selected from (a-1), (a-2) or (a-3), or is a group of formula (b-1), i.e., -Z-; s is 0, 1 or 2; R6 is -CHO, C1-6alkyl, piperidinyl-C1-6alkyl, arylcarbonylpiperidinyl-C1-6alkyl or arylalkyl (C6-6) - (C1-6alkylamino-C1-6alkyl; R8 is alkyl) of d-6, when R3 is a group of formula (b-1), then Z is a heterocyclic ring system selected from (c-2) or (c-4), and each R10 is independently hydrogen, C1-alkyl -6 or (C 1-6) alkyloxy-C 1-6 alkylamino 3.- The compound according to claim 1 and claim 2, further characterized in that n is 0; X is N or CR 5, wherein R 5 is hydrogen R1 is d6 alkyl, R2 is hydrogen or hydroxy, or together with R can form = O; R is a radical selected from (a-1) or (a-2); s is O or; R6 is - CHO or C 1-6 alkyl, and R 4 is hydrogen, C 1-6 alkyl or 4. The compound according to claims 1, 2 and 3, further characterized in that it is selected from compound No.1, compound No. 5, compound No. 7, compound No. 3 and compound No.17: compound 5 compound 3 compound 17 5. The compound according to any of claims 1 to 4, further characterized in that it is used as a medicine. 6. A pharmaceutical composition comprising pharmaceutically acceptable carriers and as an active ingredient a therapeutically effective amount of a compound as claimed in claims 1 to 4. 7. The use of a compound of formula (I) for the preparation of a medicament for the treatment of a PARP-mediated disorder, wherein said compound of formula (I) is: the? / -oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein: n is 0, 1 or 2; X is N or CR5, wherein R5 is hydrogen, or together with R1 can form a bivalent radical of formula -CH = CH-CH = CH-; R1 is d-6 alkyl or thienyl; R2 is hydrogen or hydroxy, or together with R3 or R4 can form = 0; R3 is a radical selected from: - (CH2) S-NR6R7 (a-1), -OH (a-2), -O-R8 (a-3), -S-R9 (a-4), or where s is 0, 1, 2 or 3; R6 is -CHO, C1-6alkyl, hydroxyC1-6alkyl, (C6-6) alkylcarbonyl, di (C1-6alkyl) -amino-C6-6alkyl, alkyloxy ( C? -6) -alkyl of C-? -6, alkyl (C? -6) -carbonylamino-C1-6alkyl, piperidinyl-aIqu? (C? -6) -aminocarbonyl, piperidinyl, piperidinyl-C? -6 alkyl, piperidinyl-a-quin (C? 6) aminocarbonyl, C? -6-alkyloxy, thienyl-C 1-6 -alkyl, pyrrolyl-C? -6 alkyl, aryl-alkyl (C? .6) -piperfinol, arylcarbonyl-C1-6alkyl, arylcarbonylpiperidinyl-C6-6alkyl, haloindozolylpiperidinyl-d-6alkyl, or aryl-alkyl (C6-6) - ( C? -6) alkyl-amino-alkyl of C.-β; R7 is hydrogen or C-β alkyl; R 8 is C 1 --6 alkyl, alkyl (d 6) carbonyl or C 1-6 alkyl-amino-C 1-6 alkyldial; and R9 is di (C6 alkyl) -amino-C6 alkyl; or R3 is a group of formula: -Z- (b-1), wherein Z is a heterocyclic ring system selected from: . { c-2} (c-3) (c-4) < or i > wherein each R 10 is, independently, hydrogen, d-6 alkyl, aminocarbonyl, hydroxy, (C? -6) -alkyloxy-d-6alkyl, (C? -6) alkyloxy-C? -6 -cykylamino, C6-6aryl-alkyl, di (phenyl-C2-6alkenyl), piperidinyl- alkyl of d-6 > C3-10 cycloalkyl, (C3-10) cycloalkyl-Ci-β alkyl, aryloxy (hydroxy) -alkyl of d.6, haloindazolyl, aryl-alkyl of d-6, aryl-alkenyl of C2-6, morpholino, alkyl (C-6) -imidazolyl, pyridinyl-alkyl (C? -6) amino; R 4 is hydrogen, C 1-6 alkyl, furanyl, pyridinyl, aryl-alkyl of d-6 or aryl is phenyl or phenyl substituted with halogen, C 1-6 alkyl or alkyloxy of d. 6- The use of a PARP inhibitor of formula (I) which is claimed in claim 7, for the preparation of a medicament for the treatment of a disorder mediated by PARP-1. 9. The use claimed in claims 7 and 8, wherein said treatment includes chemosensitization. 10. The use claimed in claims 7 and 8, wherein said treatment includes radiosensitization. 11. A combination of a compound with a chemotherapeutic agent, wherein said compound of formula (I) is: the? / -oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein: n is 0, 1 or 2; X is N or CR5, wherein R5 is hydrogen, or together with R1 can form a bivalent radical of formula -CH = CH-CH = CH-; R1 is C1-6 alkyl or thienyl; R2 is hydrogen or hydroxy, or together with R3 or R4 can form = O; R3 is a radical selected from: - (CH2) S-NR6R7 (a-1), OH (a-2), • O-R8 (a-3), S-R9 (a-4), or C = N (a-5), where s is 0, 1, 2 or 3; R6 is -CHO, C1-6alkyl, hydroxyC1-6alkyl, alkyl (C6-6) -carbonyl, di (C1-6alkyl) -amino-C1-6alkyl, alkyloxy ^ dd) -alkyl of C? _6, alkyl (d-6) -carbonylamino-C1-6alkyl, piperidinyl-C1-6alkylaminocarbonyl, piperidinyl, piperidinyl-C1-6alkyl, piperidinyl-alkyl (C? _6) aminocarbonyl, C? -6 alkyloxy, thienyl-C? -6 alkyl, pyrrolyl-C? -6 alkyl, aryl-aiqui Ci-e piperidinyl, arylcarbonyl-d-6 alkyl, arylcarbonylpiperidinyl -alkyl of d-6, haloindozolylpiperidinyl-alkyl of d-6, or aryl-alkyl (C.-6) - (a, cu of d-ene-amino-alkyl of C? -6l R7 is hydrogen or alkyl of C? -6; R8 is C? .6 alkyl, (C? 6) alkylcarbonyl or di (C? -6 alkyl) -amino-G? -6 alkyl, and R9 is di (alkyl) C? -6) -amino-alkyl of d-6; or R3 is a group of the formula: -Z- (b-1), wherein Z is a heterocyclic ring system selected from: (c- 1) (c-2) < c-3) (c-4) wherein each R 10 is, independently, hydrogen, d. »aminocarbonyl, hydroxy, - alkane iil (Ct C 1-6 alkyloxy-C 1-6 alkyl, C 1-6 alkyloxy-dyalkylamino-amino, C 1-6 arylalkyl, di (phenyl-C 2-6 alkenyl), piperidinyl-alkyl of d-6, C3-10 cycloalkyl. C3-1o cycloalkyl-C1-6 alkyl. aryloxy (hydroxy) -Cl6 alkyl, haloindazolyl, aryl-C6-alkyl, aryl-C2-6 alkenyl. morpholino, (C 1-6) alkyl-imidazolyl, or pyridinyl-alkyl (C? -6) amino; R 4 is hydrogen, d-6 alkyl, furanyl, pyridinyl, alkyl (C 6 -aryl), or aryl is phenyl or phenyl substituted by halogen, C? -6 alkyl or C1-6 alkyloxy. 12. A process for preparing a compound as claimed in claim 1, characterized in that it comprises: (a) the hydrolysis of the intermediates of formula (VIII) according to known methods, subjecting the intermediates of formula (VIII) ) to the appropriate reagents, such as tin chloride, acetic acid and hydrochloric acid, in the presence of an inert reaction solvent, for example tetrahydrofuran: (VID) (i) (b) cyclization of the intermediates of formula (X) according to known cyclization procedures, to form the compounds of formula (I) wherein X is CH, referred to herein as the compounds of formula (Ij), preferably in the presence of a suitable Lewis acid, for example aluminum chloride , either neat or in a suitable solvent, such as for example an aromatic hydrocarbon, for example benzene, chlorobenzene, methylbenzene and the like; halogenated hydrocarbons, for example trichloromethane, tetrachloromethane and the like; an ether, for example tetrahydrofuran, 1,4-dioxane and the like, or mixtures of said solvents: (X) a-j) (c) the condensation of an appropriate ortho-benzenediamine of formula (XI) with an ester of formula (XII) wherein Rh is d-6 alkyl, to form the compounds of formula (I) wherein X is N, referred to here as the compounds of formula (I), in the presence of a carboxylic acid, for example acetic acid and the like, a mineral acid such as for example hydrochloric acid, sulfuric acid, or a sulfonic acid such as for example methanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid and the like.