MXPA06006573A - Substituted 6-cyclohexylalkyl substituted 2-quinolinones and 2-quinoxalinones as poly(adp-ribose) polymerase inhibitors - Google Patents
Substituted 6-cyclohexylalkyl substituted 2-quinolinones and 2-quinoxalinones as poly(adp-ribose) polymerase inhibitorsInfo
- Publication number
- MXPA06006573A MXPA06006573A MXPA/A/2006/006573A MXPA06006573A MXPA06006573A MX PA06006573 A MXPA06006573 A MX PA06006573A MX PA06006573 A MXPA06006573 A MX PA06006573A MX PA06006573 A MXPA06006573 A MX PA06006573A
- Authority
- MX
- Mexico
- Prior art keywords
- alkyl
- hydrogen
- formula
- compound
- alkyloxy
- Prior art date
Links
- 230000002401 inhibitory effect Effects 0.000 title claims abstract description 44
- 239000003112 inhibitor Substances 0.000 title claims abstract description 28
- 102000012338 Poly(ADP-ribose) Polymerases Human genes 0.000 title description 2
- 108010061844 Poly(ADP-ribose) Polymerases Proteins 0.000 title description 2
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2(1H)-one Chemical class C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 title 1
- FFRYUAVNPBUEIC-UHFFFAOYSA-N quinoxalin-2-ol Chemical class C1=CC=CC2=NC(O)=CN=C21 FFRYUAVNPBUEIC-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 190
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 claims abstract description 55
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- XBDQKXXYIPTUBI-UHFFFAOYSA-M propionate Chemical class CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- SMWDFEZZVXVKRB-UHFFFAOYSA-N quinoline Chemical group N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 1
- 150000003252 quinoxalines Chemical group 0.000 description 1
- 239000002534 radiation-sensitizing agent Substances 0.000 description 1
- 230000001603 reducing Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 201000001365 retinal ischemia Diseases 0.000 description 1
- 201000000582 retinoblastoma Diseases 0.000 description 1
- 150000003902 salicylic acid esters Chemical class 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 231100000202 sensitizing Toxicity 0.000 description 1
- 230000001235 sensitizing Effects 0.000 description 1
- 231100000486 side effect Toxicity 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- WQDUMFSSJAZKTM-UHFFFAOYSA-N sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 1
- ODGROJYWQXFQOZ-UHFFFAOYSA-N sodium;boron(1-) Chemical compound [B-].[Na+] ODGROJYWQXFQOZ-UHFFFAOYSA-N 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000002195 synergetic Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 150000003899 tartaric acid esters Chemical class 0.000 description 1
- 229930003347 taxol Natural products 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 230000001225 therapeutic Effects 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N tin hydride Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical class CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- 239000000700 tracer Chemical class 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-M trichloroacetate Chemical class [O-]C(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-M 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 230000001573 trophoblastic Effects 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- PODBBOVVOGJETB-UHFFFAOYSA-N zinc phthalocyanine Chemical compound N1=C2C3=CC=CC=C3C(N=C3C4=CC=CC=C4C(=N4)N33)=[N]2[Zn]23N3C1=C1C=CC=CC1=C3N=C1[N]2=C4C2=CC=CC=C21 PODBBOVVOGJETB-UHFFFAOYSA-N 0.000 description 1
- OBBCSXFCDPPXOL-UHFFFAOYSA-N α-(methoxymethyl)-2-nitro-1H-Imidazole-1-ethanol Chemical compound COCC(O)CN1C=CN=C1[N+]([O-])=O OBBCSXFCDPPXOL-UHFFFAOYSA-N 0.000 description 1
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, s, R1, R2, R3, Q, X and Y have defined meanings.
Description
2-QUINOLINONES AND 2-QUINOXAHNONAS SUBSTITUTED WITH 6-CYCLOHEX1LALKYL REPLACED AS POH.ADENOSIN-5'-DIFOSFO-RIBOSA INHIBITORS) POLYMERASE
FIELD OF THE INVENTION
The present invention relates to PARP and provides compounds and compositions containing the described compounds. Moreover, the present invention provides methods for using the PARP inhibitors described 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 enzyme family consisting 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 major nuclear protein of 116 kDa consisting of three domains: the N-terminal DNA binding domain containing two zinc projections, the ato-modification 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 approximately 200 units of ADP-ribose. The protein acceptors 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 Ca + - and Mg2 + - dependent endonucleases. The PARP portion is expressed at a high level in many tissues, most notably in the immune system, heart, brain and germline cells. Under normal physiological conditions, there is minimal PARP activity. However, DNA damage causes an immediate activation of PARP up to 500 times. Among the many functions attributed to PARP, and essentially
PARP-1, is its main role in facilitating DNA repair by ADP ribosylation and therefore coordination of a number of DNA repair proteins. As a result of PARP activation, NAD + levels decline significantly. The activation of extensive 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 rapid exchange rate. Once poly (ADP-ribose) is formed, it is rapidly degraded by 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 + to ADP-ribose. In less than an hour, overstimulation of PARP can cause a fall of NAD + and ATP to less than 20% of the normal level. This scenario is especially harmful during ischemia when oxygen deprivation has already drastically compromised the production of cellular energy. Subsequent free radical production during reperfusion is assumed to be a major cause of tissue damage. Part of the fall in ATP, which is typical of many organs during ischemia and reperfusion, could be linked to NAD + depletion due to the replacement of poly (ADP-ribose). Therefore, it is expected that the PARP or PARG inhibitors preserve the level of cellular energy thus enhancing the survival of ischemic tissues after an attack. The synthesis of poly (ADP-ribose) is also involved in the induced expression of a number of genes essential for inflammatory response. PARP inhibitors suppress the production of inducible nitric oxide synthase (NOS) in macrophages, P-type selectin and intracellular adhesion molecule-1 (ICAM-1) in endothelial cells. This activity is based on the strong anti-inflammatory effects presented by 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 attachment of up to 100 units of ADP-ribose to a variety of nuclear proteins, including histones and the PARP itself. During increased cellular stress, extensive activation of PARP can rapidly lead to cell damage or cell death through depletion of energy stores. Since four molecules of ATP are consumed by each molecule of regenerated NAD +, NAD + is depleted by activation of massive PARP, in the effort to resynthesize NAD +, ATP can also be depleted. It has been reported that activation of PARP plays a key role in NMDA- and NO- induced neurotoxicity. This has been demonstrated in cortical and hippocampal slices where the prevention of toxicity is directly related to the potency of PARP inhibition. The potential role of PARP inhibitors in the treatment of neurodegenerative diseases and head trauma has been recognized even when the exact mechanism of action has not been elucidated. Similarly, it has been shown that individual injections of PARP inhibitors have reduced the infarct size 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 occlusion or one minute before reperfusion, caused similar reductions in infarct size in the heart (32- 42%) while 1,5-dihydroxyisoquinoline (1 mg / kg), another PARP inhibitor, reduced the infarct size by a comparable degree (38-48%). These results make it reasonable to assume that PARP inhibitors could save the previously ischemic heart or damage by reperfusion of skeletal muscle tissue. Activation of PARP can also be used as a measure of damage after neurotoxic attacks resulting from exposure to any of the following inducers such as glutamate (through NMDA receptor stimulation), reactive oxygen intermediates, β-amyloid 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 have continued to explore the role of PARP activation in cerebellar granular cells in vitro and in MPTP neurotoxicity. Excessive neural exposure to glutamate, which serves as the predominant central nervous system neurotransmitter and acts as the receptors for N-meti-D-aspartate (NMDA) and other subtype receptors, very often occurs as a result of stroke or other neurodegenerative process. Oxygen-deprived neurons release glutamate in greater amounts during ischemic stroke such as during a stroke or heart attack. This excessive release of glutamate in turn causes overstimulation (excitotoxicity) of N-methyl-D-aspartate (NMDA), AMPA, kainate receptors and MGR, which open ion channels and allow the flow of uncontrolled ions (v.gr ., Ca2 + and Na + towards the interior of the cells and K + towards the outside of the cells) leading to overstimulation of the neurons. Overstimulated neurons secrete more glutamate, creating a loop of feedback or domino effect that ultimately results in cell damage or death through the production of proteases, lipases and free radicals. Excessive activation of glutamate receptors has been implicated in several 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 loss. neural after hypoxia, hypoglycemia, ischemia, trauma and nervous attack. Exposure to and stimulation of glutamate has also been implicated as a basis for compulsive disorders, particularly drug dependence. 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 so that it does not bind to or activate its receptor) block neural damage after the stroke . Attempts to prevent excitotoxicity by blocking NMDA, AMPA, kainate receptors and MGR have proven difficult because each receptor has multiple sites to which glutamate can bind and thus find an effective mixture of universal antagonists or antagonists for avoiding glutamate binding to all receptors and allowing testing this theory has been difficult. Moreover, many of the compositions that are effective in blocking the receptors are also toxic to animals. As such, there is currently no known effective treatment for glutamate abnormalities. The stimulation of NMDA receptors by glutamate, for example, activates the enzyme nitric oxide synthase (nNOS), leading to the formation of nitric oxide (NO), which is also a mediator of neurotoxicity. The neurotoxicity of NMDA can be prevented by treatment with nitric oxide synthase (NOS) inhibitors or through directed genetic modification 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, such as that induced by chronic constriction injury (CCI) of the common sciatic nerve and in which the alteration occurs. transináptica of the dorsal horn of the spinal cord characterized by cytoplasm and nucleoplasm hyperchromatosis (also called neurons
"dark"). There is also evidence that PARP inhibitors are useful for the treatment of inflammatory bowel disorders, such as colitis. Specifically, colitis was induced in rats by intraluminal administration of the hapten trinitrobenzenesulfonic acid in 50% ethanol. The treated rats received 3-aminobenzamide, a specific inhibitor of PARP activity. The inhibition of PARP activity reduced the inflammatory response and recovered the morphology and energy status of the distal colon. Additional evidence suggests that PARP inhibitors are useful for the treatment of arthritis. In addition, PARP inhibitors appear to be useful for the treatment of diabetes. PARP inhibitors have been shown to be useful for the treatment of endotoxic shock or septic shock. PARP inhibitors have also been used to prolong the life and proliferative capacity of cells including the treatment of diseases such as skin aging, Alzheimer's disease, atherosclerosis, osteoarthritis, osteoporosis, muscular dystrophy, skeletal muscle degenerative disease involving replicative senescence, muscle degeneration associated with age, immune senescence, AIDS, and other immune senescence disease; and to alter gene expression of senescent cells. It is also known that PARP inhibitors, such as 3-aminobenzamide, affect the overall 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 methylating agents, topoisomerase I inhibitors and other chemotherapeutic agents. as cisplatin and bleomycin. A variety of studies with the use of "knockout" mice, models of trans-dominant inhibition (overexpression of binding domain)
DNA), antisense and small molecular weight inhibitors have shown that the role of PARP in cell repair and survival after the induction of DNA damage. The inhibition of PARP enzymatic activity would lead to an increased sensitivity of tumor cells towards DNA damage treatments. PARP inhibitors have been reported to be effective in the radiosensitization (hypoxic) of tumor cells and effective in preventing tumor cells from recovering potentially lethal and sublethal DNA damage after radiation therapy, presumably because of their ability to avoid breaking of strands of DNA that re-join and affecting several signaling pathways of DNA damage. PARP inhibitors have been used for the treatment of cancer. In addition, the patent of E.U.A. No. 5,177,075 discloses 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), describes inhibition. of PARP activity, reduced proliferation of tumor cells and a marked synergistic effect when the tumor cells are co-treated with an alkylating agent.A recent comprehensive review of the most advanced technique has been published by Li and Zhang in IDrugs 2001, 4 ( 7): 804-812 There remains a need for effective and potent PARP inhibitors, and very particularly PARP-1 inhibitors that produce minimal side effects The present invention provides compounds, compositions and methods for inhibiting PARP activity for treatment of cancer and / or prevention of cellular, tissue and / or organ damage resulting from cell damage or death due to, for example, necrosis or apoptosis The compounds and compositions of the present invention are especially useful for increase the effectiveness of chemotherapy and radiotherapy where a main effect of the treatment is to cause DNA damage in the target cells.
TECHNICAL BACKGROUND
EP 371564, published June 6, 1990, describes quinoline, quinazoline or quinoxaline derivatives substituted with (1H-azol-1-ylmethyl). These described compounds suppress the elimination of retinoic acids in the plasma. In particular, 6- (cyclohexyl-1-and-imidazol-1-ylmethyl) -3-methyl-2 (1H) -quinoxalinone (compound A) is described.
Compound A
DETAILED DESCRIPTION OF THE INVENTION
This invention relates to compounds of the formula (I)
the N-oxide forms, the addition salts and the stereochemical isomeric forms thereof, wherein n s O or 1; s is O or 1; X is -N = or -CR4 = wherein R4 is hydrogen or taken together with R1 can form a bivalent radical of the formula -CH = CH-CH = CH-; And it's -N < or -CH <; Q is -NH-, -O-, -C (O) -, -CH2-CH2- or -CHR5-, wherein R5 is hydrogen, hydroxy, C? -6 alkyl. C6.6 arylalkyl, C1.6alkyloxycarbonyl, C1-6alkyloxy C1-6alkylamino or halogenindazolyl; R1 is C6-6 alkyl or thienyl; R2 is hydrogen or taken together with R3 can form = O; R3 is hydrogen, C-? -6 alkyl or a radical selected from -NR6R7 (a-1), -OH (a-2), -O-R8 (a-3), -S-R9 (a-4) ), or - C = N (a-5), wherein R6 is -CHO, C? -6 alkyl, hydroxyalkyl of C? "6, C1-6 alkylcarbonyl, di (C? .6 alkyl) am. C 1-6 alkyl, C 1-6 alkylcarbonylamino, C? -6 alkyl, piperidinylalkyl C 1-6, piperidinylalkylaminocarbonyl C 1-6, C 1-6 alkyloxy, C 1-6 alkyloxy C 1-6 alkyl -6, thienylalkyl of C -.- 6. pyrrollalkyl of C? -6, arylalkylpiperidinyl of C1-6, arylcarbonylalkyl of C? -6, arylcarbonylpiperidinylalkyl of C? -6. halogenoindozolylpiperidinylalkyl of C? -6, or arylalkyl of C 1-6 (C? -6 alkyl) aminoalkyl of d-?; and R7 is hydrogen or C6 alkyl; R 8 is C 1-6 alkyl, C? -6 alkylcarbonyl or C 1-6 alkylamino (C 1-6 alkyl) arninoalkyl; and R9 is di (C6-alkyl) aminoalkyl of C6-6; or R3 is a group of the formula - (CH2) t-Z- (b-1), wherein t is O, 1 or 2; Z is a heterocyclic ring system selected from
(c-)) (c-2) (c-3) (c-4)
(c-9) (c-10) (-U) (c-12) (c-13)
wherein each R10 independently is hydrogen, C -? - 6 alkyl, aminocarbonyl, hydroxy, - - alkanediyl
C6-6alkyloxy-C1-6alkyl, C6-6alkylaxy-C6-6alkylamino> < RTI > di (C2-6 phenylalkenyl), piperidinylalkyl of C6-6, cycloalkyl of C3-101 cycloalkyl of C3-? 0-C6-6alkyl, aryloxy (hydroxy) C6-6alkyl, halogenoindazolyl, arylalkyl C? -6, C2-6 arylalkenyl. morpholino, C? -6 alkylimidazolyl, or C-i-pyridinylalkylamino; each R 11 is independently hydrogen, hydroxy, piperidinyl or aryl; aryl is phenyl or phenyl substituted with halogen, C 1-6 alkyl or Cie alkyloxy with the proviso that 6- (cyclohexyl-1 - / - imidazol-1-methylmethyl) -3-methyl-2 (1 - /) - quinoxalinone. Provided that the heterocyclic ring system Z contains a portion -CH2-, -CH =, or -NH-, the substituents R10 and R11 or the remainder of the molecule can be attached to the carbon or nitrogen atom in which case one or both Hydrogen atoms are replaced. The compounds of the formula (I) may also exist in their tautomeric forms. Said forms, although not explicitly indicated in the above formula, are intended to be included within the scope of the present invention. A number of terms used in the above definitions and hereinafter are explained below. These terms are sometimes used as such or in combination terms. As used in the above definitions and below, halogen is generic for fluoro, chloro, bromo and iodo; C- | 6 alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as, e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, 1-methylethyl, -methylpropyl, 2-methyl-butyl, 2-methylpentyl and the like; C6-alkanediyl 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 the branched isomers thereof such as 2-methylpentanediyl, 3-methylpentanediyl, 2,2-dimethylbutanediyl, 2,3-dimethylbutanediyl and the like; trihalogenomethyl defines methyl containing three identical or different halogen substituents, for example trifluoromethyl; C2-6 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, 3-pentenyl , 3-methyl-2-butenyl, and the like; and C3-10 cycloalkyl include 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 that the compounds of the formula (I) are capable of forming with organic or inorganic bases such as amines, alkali metal bases and alkaline earth metal bases, or quaternary ammonium bases, or with organic and inorganic acids such as mineral acids, sulfonic acids, carboxylic acids or phosphorus-containing acids. The term "addition salt" further comprises 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 acidic or basic addition salts. The pharmaceutically acceptable acid or basic addition salts as mentioned above comprise the non-toxic acid addition and non-toxic base addition salt forms which the compounds of the formula (I) are capable of forming. The compounds of the formula (I) having basic properties can be converted to 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, e.g., hydrochloric or hydrobromic acid; sulfuric acids; nitric; phosphoric and the like; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic (ie, butanedioic), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p -Toluenesulfonic, cyclic, salicylic, p-aminosalicylic, pamoic and the like. The compounds of the formula (I) having acidic properties can be converted to their pharmaceutically acceptable basic addition salts by treating the acid form with a suitable organic or inorganic base. Suitable basic salt forms comprise, for example, ammonium salts, alkali metal or alkaline earth metal salts, e.g., lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, .gr., the benzathine,? / - methyl-D-glucamine salts, hydrabamine salts and salts with amino acids such as, for example, arginine, lysine and the like. The term "acidic or basic addition salt" also comprises the hydrates and the solvent addition forms that the compounds of the formula (I) are capable of forming. Examples of such forms are, e.g., hydrates, alcoholates and the like. The term "metal complexes" means a complex formed between a compound of the formula (I) and one or more organic or inorganic salts. Examples of said organic or inorganic salts comprise halides, nitrates, sulfates, phosphates, acetates, trifluoroacetates, trichloroacetates, propionates, tartrates, sulfonates, e.g., methyl sulfonates, 4-methylphenylsulfonates, salicylates, benzoates and the like of the metals of the second group principal of the periodic system, eg, the magnesium or calcium salt, of the third or fourth main group, eg, aluminum, tin, lead, as well as the first to the eighth periodic system transition group such as, for example, chromium, manganese, iron, cobalt, nickel, copper, zinc and the like.
The term stereochemically isomeric forms of compounds of the formula (I), as used herein, define all possible compounds made from the same atoms linked by the same sequence of bonds but having different three-dimensional structures that are not interchangeable, than the compounds of the formula (I) can possess. Unless otherwise mentioned or indicated, the chemical designation of a compound encompasses the mixture of all possible stereochemically isomeric forms that the compound may possess. Said mixture can contain all diastereomers and / or enantiomers of the basic molecular structure of said compound. As is common in pharmacology, one enantiomer may have a better pharmacological activity than the other. All stereochemically isomeric forms of the compounds of the formula (I) both in pure form and in admixture with one another are intended to be encompassed within the scope of the present invention. The? / -oxide forms of the compounds of the formula (I) are intended to encompass those compounds of the formula (I) wherein one or several nitrogen atoms are oxidized to the so-called? / -oxide, particularly those? / - oxides in where one or more of the piperidine, piperazine or pyridazinyl nitrogens are? / - oxidized. Whenever used further, the term "compounds of the formula (I)" is also intended to include all forms of N-oxide, pharmaceutically acceptable acid or basic addition salts and all stereoisomeric forms.
The compounds described in EP 371564 suppress the elimination of retinoic acids in plasma. 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 those compounds of the formula (I) wherein one or more of the following restrictions apply: a) X is -N = or -CH =; b) R1 is C-? -6 alkyl; c) R3 is hydrogen, C-i-e alkyl, a radical selected from (a-1), (a-2), (a-3) or (a-4) or a group of the formula (b-1); d) R6 is di (C? -6) aminoalkyl of C? -6 or C? -6-alkyloxy of C? -6 alkyl; e) R7 is hydrogen; f) R8 is di (C-? 6 -alkyl) aminoalkyl of g) t is 0 or 2; h) Z is a heterocyclic ring system selected from (c-1), (c-5), (c-6), (c-8), (c-10), (c-12) or (c-) 13); i) each R 10 independently is hydrogen, d-β alkyl, hydroxy, C 1-6 alkyloxy-Ci-β alkyl, Ci-β-alkylamino of C?. β alkyloxy, morpholino, C? -6 alkylimidazolyl, or C 1-6 pyridinylalkylamino; j) each R11 independently is hydrogen or hydroxy; and k) aryl is phenyl. A second group of compounds of interest consists of those compounds of the formula (I) wherein one or more of the following restrictions apply: a) n is 0; b) X is CH; c) Q is -NH-, -CH2-CH2- or -CHR5-, wherein R5 is hydrogen, hydroxy, or arylalkyl of C-i-β; d) R1 is C6.6 alkyl; e) R2 is hydrogen; f) R3 is hydrogen, hydroxy or a group of the formula (b-1); g) t is 0; h) Z is a heterocyclic ring system selected from (c-8) or (c-13); i) each R10 independently is hydrogen; j) aryl is phenyl. A third group of compounds of interest consists of those compounds of the formula (I), the first group of compounds of interest or the second group of compounds of interest wherein Z is a heterocyclic ring system other than the heterocyclic ring system of the formula (c-2) or (c-4). A group of preferred compounds consists of those compounds of the formula (I) wherein X is -N = or -CH =; R1 is Ci-β alkyl; R3 is hydrogen, C? -6 alkyl, a radical selected from (a-1), (a-2), (a-3) or (a-4) or a group of the formula (b-1); R6 is di (C1-6 alkyl) aminoalkyl of C-? -6 or C6-6 alkyloxy-C6-alkyl; R7 is hydrogen; Rd is di (C-? 6 alkyl) aminoalkyl of C-I-T; t is 0 or 2; Z is a heterocyclic ring system selected from (c-1), (c-5), (c-6), (c-8), (c-10), (c-12) or (c-13); each of R10 independently is hydrogen, C- [alpha] -6 alkyl, hydroxy, C- [alpha] -6-oxyalkyl-C6-alkyl, C6-oxyalkyl-Ci-b-amino alkyl, morpholino, Ci-β alkylimidazolyl, or C? -6 pyridinyl-alkylamino; each of R11 independently is hydrogen or hydroxy; and aryl is phenyl. An additional group of preferred compounds consists of those compounds of the formula (I) wherein n is 0; X is CH; Q is -NH-, -CH2-CH2- or -CHR5-, wherein R5 is hydrogen, hydroxy or arylalkyl of C? -6; R1 is Ci-β alkyl; R2 is hydrogen; R3 is hydrogen, hydroxy or a group of the formula (b-1); t is 0; Z is a heterocyclic ring system selected from (c-8) or (c-13); each R10 independently is hydrogen; and aryl is phenyl. An additional group of preferred compounds consists of those compounds of the formula (I), the group of preferred compounds or the additional group of preferred compounds wherein Z is a heterocyclic ring system other than the heterocyclic ring system of the formula (c) 2) or (c- 4). The most preferred compounds are compound No 7, compound No 2, compound No 1 and compound No 11.
The compounds of the formula (I) can be prepared according to the general methods described in EP 371564. A number of said methods of preparation will be described in more detail below. Other methods for obtaining final compounds of the formula (I) are described in the examples. The compounds of the formula (I) wherein R2 is hydrogen and R3 is -NR7-CHO wherein R7 is hydrogen or methyl, referred to herein as compounds of the formula (lb), can be prepared starting from the compounds of the formula (I), wherein R2 taken together with R3 form = O, here referred to as compounds of the formula (Ia), in the presence of formamide or methylformamide, here indicated as intermediates of the formula (II), and formic acid.
The compounds of the formula (1), wherein R 3 is hydroxy, here referred to as compounds of the formula (1c), can be prepared by converting the ketone portion of the compounds of the formula (Ia) to a hydroxy group, with a reductant suitable, e.g., sodium borohydride in a suitable solvent, e.g. methanol and tetrahydrofuran.
The compounds of the formula (Ia) can be prepared by converting the compounds of the formula (Ic), wherein R 2 is hydrogen, here referred to as compounds of the formula (I-1), in the presence of a suitable oxidant such as trioxide. chromium and an acid such as sulfuric acid, in a suitable solvent such as 2-propanone.
Intermediates of the formula (IV), wherein W is an appropriate residual group such as, for example, chloro, bromo, methanesulfonyloxy or benzenesulfonyloxy can be prepared from compounds of the formula (Ic-1) by treating said compounds with a reagent suitable, e.g., methanesulfonyloxy chloride or benzenesulfonyloxy chloride, or a halogenating reagent such as e.g., POCI3 or SOCI2.
Compounds of the formula (I), defined as compounds of the formula (I) wherein Rb is as defined in R6 and Rc is as defined in R7, or R and Rc taken together with the nitrogen to which they are attached, form an appropriate heterocyclic ring system as defined in Z, herein referred to as compounds of the formula (Ih), can be prepared by reacting an intermediate of the formula (IV) with an intermediate of the formula (V). The reaction can be carried out in a reaction inert 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 the formula (I) can also be converted to one another through reactions known in the art or functional group transformations. A number of these transformations have already been described above. Other examples are hydrolysis of carboxylic esters of the corresponding carboxylic acid or alcohol; hydrolysis of amides to the corresponding carboxylic acids or amines; hydrolysis of nitriles to the corresponding amides; amino groups on imidazole or phenyl can be replaced by a hydrogen by diazotization reactions known in the art and subsequent replacement of the diazo group by hydrogen; the alcohols can be converted to esters and ethers; the primary amines can be converted to secondary or tertiary amines; the double bonds can be hydrogenated to the corresponding individual link; an iodo radical on a phenyl group can be converted to an ester group by insertion of carbon monoxide in the presence of a suitable palladium catalyst. Here, the compounds of the formula (I), (I-a), (1-b), (1-c), (1-c-1), (I-h) > ('-. (H) and (lk) may optionally be the subject of one or more of the following conversions in any desired order: (i) converting a compound of the formula (I) to a compound other than the formula (I) ), (ii) converting a compound of the formula (I) to the acceptable salt or corresponding N-oxide thereof, (iii) converting a pharmaceutically acceptable salt or N-oxide of a compound of the formula (I) to the parent compound. of the formula (I): (iv) preparing a stereochemically isomeric form of a compound of the formula (I) or a pharmaceutically acceptable salt or N-oxide thereof.
The intermediates of the formula (VII), where Rd and Re are appropriate radicals or taken together with the carbon to which they are attached, form an appropriate heterocyclic ring system as defined in Z, can be prepared by hydrolyzing intermediates of the formula ( VI), wherein R3 is a group of the formula (b-1) or a radical of the formula (a-1) wherein s is other than 0, here referred to as R9, in accordance with methods known in the art, such as agitation of the intermediate (VI) in an aqueous acid solution in the presence of a solvent inert to the reaction, e.g., tetrahydrofuran. A suitable acid is, for example, hydrochloric acid.
The compounds of the formula (I) wherein R 2 is hydrogen and R 9 is as defined above, here referred to as compounds of the formula (1 k), can be prepared starting from intermediates of the formula (VII), by selective hydrogenation of the intermediate with an appropriate reducing agent such as, for example, with a noble catalyst, such as platinum on carbon, palladium on carbon and the like and an appropriate reductant such as hydrogen in a suitable solvent such as methanol.
(VII) (HO
The compounds of the formula (I) can be prepared by hydrolyzing intermediates of the formula (VIII), according to methods known in the art, by subjecting the intermediates of the formula (VIII) to appropriate reagents, such as, tin chloride, acid acetic acid and hydrochloric acid, in the presence of a solvent inert to the reaction, e.g., tetrahydrofuran.
(VII I) (D The compounds of the formula (I) can be prepared starting from N-oxides of the formula (IX) by converting the intermediates of the 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.
x-0) The compounds of the formula (I) wherein X is CH, here referred to as compounds of the formula (I-j), can also be obtained by cyclizing an intermediate of the formula (X). The cyclization reaction of intermediates of the formula (X) can be conducted in accordance with cyclization procedures known in the art. Preferably, the reaction is carried out in the presence of a suitable Lewis acid, e.g., aluminum chloride either in net form or in a suitable solvent such as, for example, an aromatic hydrocarbon, e.g. benzene, chlorobenzene, methylbenzene and the like; halogenated hydrocarbons, e.g., trichloromethane, tetrachloromethane and the like; an ether, e.g., tetrahydrofuran, 1,4-dioxane and the like; or mixtures of said solvents. Temperatures a little high, preferably between 70 ° -100 ° C, and agitation can increase the reaction rate.
(X) fl-j)
The compounds of the formula (I), wherein X is N, here referred to as compounds of the formula (li), can be obtained by condensing an appropriate ortho-benzenediamine of the formula (XI) with an ester of the formula (XII) , wherein Rh is C? -6 alkyl. The condensation of the substituted ortho-diamine of the formula (XI) and the ester of the formula (XII) can be carried out in the presence of a carboxylic acid, e.g., 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. Slightly elevated temperatures may be appropriate for increasing the reaction rate and in some cases the reaction may be carried out at the reflux temperature of the reaction mixture. The water that is released during the condensation can be removed from the mixture by azeotropic distillation, distillation and similar methods.
< XD (XII) C-j
The intermediates of the formula (XI) can be prepared by a nitro to amine reduction reaction starting with an intermediate of the formula (Xlll) in the presence of a metal catalyst such as Raney nickel and an appropriate reductant such as hydrogen in a suitable solvent such as methanol.
(xm) (XD
The intermediates of the formula (Xlll) can be prepared by hydrolyzing intermediates of the formula (XIV), according to methods known in the art, such as by stirring the intermediate (XIV) in an aqueous acid solution in the presence of a solvent inert to the reaction, v.gr. tetrahydrofuran. A suitable acid is, for example, hydrochloric acid.
sav) can)
The intermediates of the formula (X) can be conveniently prepared by reacting an aniline of the formula (XV) with a halogenide of the formula (XVI) in the presence of the base such as pyridine in a suitable solvent such as dichloromethane. or R2 W-O-CR ^ CH-C ^ R2
(XV) (X)
The intermediates of the formula (VIII) wherein n is 0, R 2 is hydrogen or hydroxy and when R 2 is hydrogen then R 3 is hydroxy, here referred to as intermediates of the formula (VI I Ia), can be prepared by treating an intermediate of the formula (XVII), wherein W is halogen, with an organolithium reagent such as, e.g., n-butyl lithium in a reaction inert solvent, e.g., tetrahydrofuran, and subsequently reacting with the intermediary with an intermediate of the formula (XVlll), wherein R1 is hydrogen or a radical as defined in R3.
The present invention also relates to a compound of the formula (I) as defined above for use as a medicine. The compounds of the present invention have PARP inhibitory properties as can be seen from the experimental part below. The present invention also contemplates the use of compounds in the preparation of a medicament for the treatment of any of the diseases and disorders in an animal described herein, wherein said compounds are a compound of the formula (I)
the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein n is 0 or 1; s is 0 or 1; X is -N = or -CR4 = where R4 is hydrogen or taken together with
R1 can form a bivalent radical of the formula -CH = CH-CH = CH-; And it's -N < or -CH <; Q is -NH-, -O-, -C (O) -, -CH2-CH2- or -CHR5-, wherein R5 is hydrogen, hydroxy, C1-6alkyl, arylalkyl of C-? 6, alkyloxycarbonyl Ci-e, C 1-6 alkyloxy-C 1-6 alkylamino or halogenoindazolyl; R1 is C1-6 alkyl or thienyl; R2 is hydrogen or taken together with R3 can form = O; R3 is hydrogen, C1-6 alkyl or a radical selected from -NR6R7 (a-1), -OH (a-2), -O-R8 (a-3), -S-R9 (a-4), or -C-N (a-5), wherein R6 is -CHO, C1-6 alkyl, C6-6 hydroxyalkyl, C6-6 alkylcarbonyl, C6-6alkylaminoalkyl di- ? -6, C? -6 alkylcarbonylamino, C1-6alkyl, piperidinylalkyl of C? -6, piperidinylalkylaminocarbonyl of C? -6, alkyloxy of C? -6, alkyloxy of C? -6- C- alkyl. -6, thienylalkyl of C1.6, pyrrolylalkyl of C? -6, arylalkylpiperidinyl of C? -6, arylcarbonylalkyl of C1-6, arylcarbonylpiperidinylalkyl of C? -6, halogenoindozolylpiperidinylalkyl of C? -6, or arylalkyl of C1-6 ( Ci. 6 alkyl) aminoalkyl of C -? - 6. and R7 is hydrogen or C1-6alkyl; R8 is C? -6 alkyl, C? -6 alkylcarbonyl or C? | 6 alkyl) aminoalkyl of C- | 6; and R9 is di (C6-alkyl) aminoalkyl of C-i-e; or R3 is a group of the formula - (CH2) rZ- (b-1), where t is 0, 1 or 2; Z is a heterocyclic ring system selected from
(c-i) (c-2) (c-3))
wherein each R10 independently is hydrogen, C1-6 alkyl. aminocarbonyl, hydroxy,
C6-6alkyloxyC6-6alkyl, C6-6alkyloxy C1.6alkyloxy, di (phenylalkenyl- d-6), piperidinylalkyl-C6-6, C3-cycloalkyl -? o > C3 cycloalkylalkyl. C1.6 alkyl, aryloxy (hydroxy) C6-6 alkyl, halogenoindazolyl, arylalkyl of d-6, arylalkenyl of C2-6, morpholino, alkylimidazolyl of C1-6, or pyridinylalkylamino of C6-6; each R11 independently is hydrogen, hydroxy, piperidinyl or aryl; the aryl is phenyl or phenyl substituted with halogen, C 1-6 alkyl or C 1-6 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 a basic or acid addition salt, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, the carrier can adopt a wide variety of shapes depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in a unit dosage form suitable, preferably, for oral, rectal, percutaneous administration, or by parenteral injection. For example, when preparing the compositions in oral dosage form, any of the oral pharmaceutical means, such as, for example, water, glycols, oils, alcohols and the like can be used in the case of oral liquid preparations such as suspensions, syrups. , elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease of administration, tablets and capsules represent the most advantageous dosage unit form, in which case solid pharmaceutical carriers are obviously used. For parenteral compositions, the vehicle will usually comprise sterile water, at least in large part, although other ingredients, for example, may be included to aid solubility. Injectable solutions can be prepared, for example, in which the vehicle comprises saline solution, glucose solution or a mixture of saline solution and glucose solution. Injectable suspensions may also be prepared in which case suitable liquid carriers, suspending agents and the like may be used. In compositions suitable for percutaneous administration, the vehicle optionally comprises a penetration enhancing agent and / or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, said additives do not cause a significant deleterious effect to the skin. Said additives may facilitate administration to the skin and / or may be useful for preparing the desired compositions. These compositions can be administered in various ways, e.g., as a transdermal patch, as a deposition, as an ointment. It is especially advantageous to formulate the aforementioned compositions in dosage unit form for ease of administration and dose uniformity. The unit dosage form as used in the specification and the claims herein refers to physically discrete 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 aforementioned pharmaceutical carrier. Examples of forms of said dosage unit are tablets (including labeled or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, tablespoons, small tablespoonfuls and the like, and segregated multiple thereof. The compounds of the present invention can treat or prevent tissue damage resulting from damage or death of cells due to necrosis or apoptosis; can alleviate damage to neural or cardiovascular tissue, including that following 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 cycle or the proliferative capacity of the cells; can alter gene expression of senescent cells; they can radiosensitize and / or chemosensitize the cells. Generally, the inhibition of PARP activity rewards energy loss cells, avoiding, in the case of neural cells, irreversible depolarization of neurons, and therefore, provides neuroprotection. For the above reasons, the present invention further relates to a method for administering a therapeutically effective amount of the above identified compounds in an amount sufficient to inhibit PARP activity, to treat or prevent tissue damage resulting from damage or death of cells due to necrosis or apoptosis, to perform a neuronal activity not mediated by NMDA toxicity, to effect neuronal activity mediated by NMDA toxicity, to treat neural tissue damage resulting from ischemia and reperfusion injury, neurological disorders and diseases neurodegenerative; to prevent or treat cerebral vascular accident; to treat or prevent cardiovascular disorders; to treat other conditions and / or disorders such as age-related muscle degeneration, AIDS and other immune diseases of senescence, inflammation, gout, arthritis, atherosclerosis, cachexia, cancer, skeletal muscle degenerative disease that involves replicative senescence, diabetes, head trauma, inflammatory bowel disorders (such as colitis and Crohn's disease), muscular dystrophy, osteoarthritis, osteoporosis, chronic and / or acute pain (such as neuropathic pain), kidney failure, retinal ischemia, septic shock (such as endotoxic shock), and aging of the skin, to prolong the life cycle and proliferative capacity of the cells; to alter gene expression of senescent cells; radiosensitization and / or chemosensitization (hypoxic) of tumor cells. The present invention also relates to the treatment of diseases and conditions in an animal that comprises administering to said animal a therapeutically effective amount of the compounds identified above. 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 disease state, traumatic brain injury, physical damage to the spinal cord, stroke 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 compounds of the formula (I) to inhibit the activity of PARP, to treat, prevent or inhibit tissue damage resulting from damage or death of cells due to necrosis or apoptosis, to treat, prevent or inhibit a neurological disorder in an animal. The term "prevention of neurodegeneration" includes the ability to prevent neurodegeneration in patients newly diagnosed with a neurodegenerative disease, or at risk of developing a new degenerative disease and to prevent subsequent neurodegeneration in patients who already suffer from or have symptoms of a neurodegenerative disease. The term "treatment", as used herein, covers any treatment of a disease and / or condition in an animal, particularly a human, and includes: (i) preventing a disease and / or condition occurring in a subject that may be predisposed to the disease and / or condition but not yet diagnosed as having it; (ii) inhibit the disease and / or condition, that is, stop its development; (iii) alleviating the disease and / or condition, i.e., causing regression of the disease and / or condition. The term "radiosensitizer", as used herein, is identified as a molecule, preferably a low molecular weight molecule, administered to animals in therapeutically effective amounts to increase the sensitivity of the cells to ionizing radiation and / or to promote the 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 treatment of ionizing radiation of other diseases not listed here is also contemplated by the present invention. 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 a chemotherapy and / or to promote the treatment of diseases. which are treatable with chemotherapy. Diseases that are treatable with chemotherapy include neoplastic diseases, benign and malignant tumors, and cancer cells. The treatment of chemotherapy of other diseases not listed here is also contemplated by the present invention. The compounds, compositions and methods of the present invention are particularly useful for treating or preventing tissue damage resulting from death or damage of cells due to necrosis or apoptosis. The compounds of the present invention can be "anti-cancer agents", the term also encompasses "tumor cell anti-growth agents" and "anti-neoplastic agents". For example, the methods of the invention are useful for treating cancers and chemosensitization and / or radiosensitization of tumor cells in cancers such as ACTH-producing tumors., Acute lymphocytic leukemia, acute nonlymphocytic leukemia, adrenocortical cancer, bladder cancer, brain cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia, chronic myelocytic leukemia, colorectal cancer, cutaneous T cells, endometrial cancer , esophageal cancer, Ewing's sarcoma, gallbladder cancer, hairy cell leukemia, head and neck cancer, Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer, liver cancer, lung cancer (small cell and / or small), malignant peritoneal effusion, malignant pleural effusion, melanoma, mesothelioma, multiple myeloma, neuroblastoma, non-Hodgkin lymphoma, osteosarcoma, ovarian cancer, ovarian (germ cell) cancer, prostate cancer, pancreatic cancer, penile cancer, retinoblastoma , skin cancer, soft tissue sarcoma, squamous cell carcinomas, stomach cancer, testicular cancer, thyroid cancer, neoplasm trophoblastic diseases, uterine cancer, vaginal cancer, cancer of the vulva and Wilm's tumor. Therefore, the compounds of the present invention can be used as "radiosensitizers" and / or "chemosensitizers". It is known that radiosensitizers increase the sensitivity of cancer cells to the toxic effects of ionizing radiation. Several mechanisms for the mode of action of radiosensitizers have been suggested in the literature including: hypoxic cell radiosensitizers (eg, 2-nitroimidazole compounds, and benzotriazine dioxide compounds of) simulating oxygen or alternatively behave like hypochlorite agents under hypoxia; non-hypoxic cell radiosensitizers (e.g., halogenated pyrimidines) can be analogs of DNA bases and are preferably incorporated into the DNA of cancer cells and therefore promote the disruption of radiation-induced DNA molecules and / or impede normal DNA repair mechanisms; and some other potential mechanisms of action have been hypothesized for radiosensitizers in the treatment of disease. Many cancer treatment protocols currently use radiosensitizers along with x-ray radiation. Examples of X-ray-activated radiosensitizers include, but are not limited to, the following: metronidazole, misonidazole, desmethylmisonidazole, pimonidazole, etanidazole, nimorazole, mitomycin C, RSU 1069, SR 4233, E09, RB 6145, nicotinamide, 5-bromodeoxyuridine ( BUdR), 5-iododeoxyuridine (lUdR), bromodeoxycytidine, fluorodeoxyuridine (FudR), hydroxyurea, cisplatin and therapeutically effective analogues and derivatives thereof. Photodynamic therapy (PDT) of cancers uses visible light as the radiation activator of the sensitizing agent. Examples of photodynamic radiosensitizers include the following, but are not limited to: hematoporphyrin derivatives, photofrina, benzoporphyrin derivatives, tin ethioporphyrin, pheoborbide-a, bacteriochlorophyll-a, naphthalocyanines, phthalocyanines, zinc phthalocyanine, and therapeutically effective analogs and derivatives thereof. The radiosensitizers can be administered together with a therapeutically effective amount of one or more other compounds, including but not limited to: compounds that promote the incorporation of radiosensitizers to the target cells; compounds that control the flow of therapeutic agents, nutrients, and / or oxygen to the target cells; chemotherapeutic agents that act on the tumor with or without additional radiation; or other therapeutically effective compounds for treating cancer or another disease. Examples of additional therapeutic agents that may be used in conjunction with radiosensitizers include, but are not limited to: 5-fluorouracil, leucovorin, d-amino-d-deoxythymidine, oxygen, carbogen, red blood cell transfusions, perfluorocarbons (e.g. , Fluosol 10 DA), 2,3- DPG, BW12C, calcium channel blockers, pentoxifylline, antiangiogenesis compounds, hydralazine, and LBSO. Examples of quiemotherapeutic agents that may be used in conjunction with radiosensitizers include, but are not limited to: adriamycin, camptothecin, carboplatin, cisplatin, daunorubicin, docetaxel, doxorubicin, interferon (alpha, beta, gamma), interleukin 2, irinotecan, paclitaxel, topotecan and therapeutically effective analogs and derivatives thereof. The chemosensitizers can be administered together with a therapeutically effective amount of one or more other compounds, including but not limited to: compounds that promote the incorporation of chemosensitizers to the target cells; compounds that control the flow of therapeutic agents, nutrients, and / or oxygen to the target cells; chemotherapeutic agents that act on the tumor or other therapeutically effective compounds to treat cancer or another disease. Examples of additional therapeutic agents that can be used in conjunction with chemosensitizers include, but are not limited to: methylating agents, toposisomerase I inhibitors and other chemotherapeutic agents such as cisplatin and bleomycin. The compounds of the formula (I) can also be used to detect or identify PARP, and very particularly the PARP-1 receptor. For that purpose, the compounds of the formula (I) can be labeled. The label can be selected from the group consisting of a radioisotope, spin marker, antigen marker, fluorescent enzyme label group or a chemiluminescent group. Those skilled in the art could easily determine the effective amount from 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, and in particular from 0.05 mg / kg to 10 mg / kg of body weight. It may be appropriate to administer the required dose as two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing 0.5 to 500 mg, and in particular 1 mg to 200 mg of active ingredient per unit dose form. The following examples illustrate the present invention.
Experimental part Hereinafter, "BuLi" is defined as butyl-lithium, "DCM" is defined as dichloromethane, "DIPE" is defined as diisopropyl ether, "DMF" is defined as N, N-dimethylformamide, "DMSO" is defined as dimethyl sulfoxide, "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 intermediaries 1 and 2
intermediate 1 intermediate 2 Aluminum chloride (0.6928 moles) was added in portions to a solution of chloroacetyl chloride (0.5196 moles) in DCM (50.2 ml) while the temperature was kept below 30 ° C. 3-Ethyl-2 (1H) -quinolinone (0.1732 moles) was added while the temperature was maintained below 30 ° C. The mixture was stirred and refluxed for 15 hours, cooled and drained in ice water. The precipitate was filtered, washed with water and taken up in DCM. The organic solution was stirred and filtered. The precipitate was dried, giving 33.5 g of intermediate 1. The filtrate was extracted. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated to dryness, giving 20.46 g of intermediate 2.
Preparing the broker 3
H Piperi Gdina (0.24 c mol) is added dropwise at room temperature to a solution of intermediate 1 and intermediate 2 in DMF (300 ml). The mixture was stirred for 5 min, emptied in water and extracted with DCM. The organic layer was separated, dried (MgSO), filtered and the solvent was evaporated to dryness. The residue (39.14 g) was purified by column chromatography on silica gel (20-45 μm) (eluent: DCM / MeOH / NH OH 96/4 / 0.2). The pure fractions were collected and the solvent was evaporated. Part (3.7 g) of the residue (13.8 g) was crystallized from 2-propanone. The precipitate was filtered, washed with diethyl ether and dried, giving 3 g of intermediate 3, melting point 190 ° C.
EXAMPLE A2
a) Preparation of the intermediary 4
NBuLi 1.6M in hexane (0.0764 moles) was added dropwise to
-60 ° C under N 2 flow to a mixture of 6-bromo-3-ethyl-2-methoxy-quinoline (0.0694 mol) in THF (185 ml). The mixture was stirred at -60 ° C for 1 hour and then added dropwise at -60 ° C to a mixture of? / -methoxy- / V-methyl-cycloheptanecarboxamide (0.0694 moles) in diethyl ether (100 ml) . The mixture was stirred at -60 ° C for 1 hour, then brought to 0 ° C, emptied into a saturated NH CI solution and extracted with EtOAc. The organic layer was separated, dried (MgSO), filtered and the solvent was evaporated. The product was used without further purification, giving 21.61 g (quant.) Of intermediate 4.
b) Preparation of the intermediary 5
A mixture of intermediate 4 (0.0694 mol) in 3N hydrochloric acid (317 ml) and THF (159 ml) was stirred and refluxed overnight. The mixture was emptied on ice, basified with a concentrated NH OH solution and extracted with EtOAc. The organic layer was separated, dried (MgSO), filtered and the solvent was evaporated. The product was used without further purification, giving 17.59 g (85%) of intermediate 5.
c) Preparation of the intermediary 6
Sodium borohydrate (0.0296 moles) was added in portions to
0 ° C under N 2 flow to a mixture of intermediate 5 (0.0591 mol) in MeOH (176 ml). The mixture was emptied on ice and extracted with DCM. The precipitate was filtered and dried. The product was used without further purification, giving 6.38 g (36%) of intermediate 6.
d) Preparation of the intermediary 7
Intermediate 6 (0.0213 mol) was added in portions at 0 ° C to thionyl chloride (32 ml). The mixture was stirred at room temperature overnight. The solvent was evaporated to dryness. The product was used without further purification, giving 6.77 g (quant.) Of the intermediate 7.
EXAMPLE A3
a) Preparation of the intermediary 8
A mixture of? / - methoxy -? / - methyl-4-nitro-benzenacetamide (0.534 moles) in MeOH (1200 ml) was hydrogenated at room temperature under a pressure of 3 bars for 1 hour with Raney nickel (60 g) as a catalyst After assimilating H 2 (3 equiv), the catalyst was filtered and the filtrate was evaporated, yielding 102 g (98%) of intermediate 8.
b) Preparation of the intermediary 9
Acetyl anhydride (1.36 mol) was added dropwise at room temperature to a mixture of intermediate 8 (0.525 mol) in DCM (100 ml). The mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with DCM. The organic layer was separated, dried (MgSO), filtered and the solvent was evaporated. The residue (151.6 g) was purified by column chromatography on silica gel (20-45 μm) (eluent: DCM / MeOH / NH 4 OH 95/5 / 0.1). The pure fractions were collected and the solvent was evaporated, yielding 32 g (26%) of the intermediate 9.
c) Preparation of the intermediate 10 H
Ixtil-lithiox 1.6 Mf (74 mrl) was added at 0 ° C under N2 flow to a mixture of intermediate 9 (0.059 mol) in THF (210 ml). The mixture was stirred at 0 ° C for 90 min, emptied in water and extracted with EtOAc. The organic layer was separated, dried (MgSO), filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (20-45 μm) (eluent: DCM / MeOH / NH 4 OH 96/4 / 0.1). The desired fractions were collected and the solvent was evaporated, yielding 7 g (33%) of intermediate 0.
d) Preparation of the intermediary 11
Fuming nitric acid (5.6 ml) was added dropwise, at a temperature below 30 ° C, to a mixture of intermediate 10 (0.037 mol) in acetyl anhydride (100 ml). The mixture was stirred at a temperature below 30 ° C for 1 hour, emptied in ice water, basified with a concentrated NH OH solution and extracted with DCM. The organic layer was separated, dried (MgSO), filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (15-35 μm) (eluent: DCM / MeOH 99/1). The desired fractions were collected and the solvent was evaporated, yielding 4 g of intermediate 11.
ei Preparing the broker 12
Sodium borohydrate (0.0187 mol) was added in portions at 5 ° C to a mixture of intermediate 11 (0.017 mol) in MeOH (50 ml). The mixture was stirred at 5 ° C, hydrolyzed with water and extracted with DCM. The organic layer was separated, dried (MgSO), filtered and the solvent was evaporated, giving
4. 2 g (quant.) Of the intermediary 12.
f) Preparing the intermediary 13
A mixture of intermediate 12 (0.0176 mol) in 2N sodium hydroxide (65 ml), THF (25 ml) and EtOH (25 ml) was stirred at room temperature for 15 hours, emptied into water and extracted with EtOAc. The organic layer was separated, dried (MgSO), filtered and the solvent was evaporated, yielding 3 g.
(86%) of the intermediary 13.
g) Preparation of the intermediary 14
Triethylamine (0.03 mol) was added at room temperature to a mixture of intermediate 13 (0.015 mol) in DCM (40 ml). Methanesulfonyl chloride (0.015 mol) was added at 0 ° C under N2 flow. The mixture was stirred at 0 ° C for 1 hour and at room temperature for 3 hours. The solvent was evaporated at room temperature. The product was used without further purification, giving (quant.) Intermediate 14.
h) Preparation of the intermediary 15
A mixture of intermediate 14 (0.015 mol), ethyl 4- piperidinecarboxylate (0.045 mol) and potassium carbonate (0.045 mol) in acetonitrile (100 ml) was stirred and refluxed for 15 hours, emptied in water and filtered. extracted with EtOAc. The organic layer was separated, dried
(MgSO), filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (15-35 μm) (eluent:
DCM / MeOH / NH 4 OH 97/3 / 0.1). The pure fractions were collected and the solvent was evaporated, yielding 0.7 g (14%) of the intermediate 15.
i) Preparation of the intermediary 16
A mixture of intermediate 15 (0.002 mole) in MeOH (50 ml) was hydrogenated at room temperature under a pressure of 3 bars for 1 hour with Raney Nickel (0.7 g) as a catalyst. After similar H2 (3 equiv), the catalyst was filtered through celite, washed with MeOH and a small amount of DCM and the filtrate was evaporated, giving 0.65 g (quant.) Of intermediate 16.
EXAMPLE A4 Preparation of the intermediary 17
1.6 M nBuLi in hexane (0.148 mol) was added dropwise at -60 ° C under N2 flow to a mixture of 6-bromo-3-ethyl-2-methoxy-quinoline (0.114 mol) in THF (500 ml) and the mixture was stirred at -60 ° C for 1 hour. Cyclohexanecarboxaldehyde (0.137 mol) in THF (100 ml) was added dropwise at -60 ° C, stirred at -60 ° C for 2 hours and then further stirred at -40 ° C for 1 hour. The mixture was emptied in saturated NH CI and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The product was used without further purification, giving 34.13 g (quant.) Of intermediate 17.
b) Preparation of the intermediary 18
A mixture of intermediate 17 (0.114 mol) in 3N hydrochloric acid (250 ml) and THF (250 ml) was stirred and refluxed for 24 hours. The mixture was cooled and DCM (200 ml) was added. The precipitate was filtered, washed with water and dried. The product was used without further purification, giving 12.5 g (39%) of intermediate 18.
c) Preparing the intermediary 19
Intermediate 18 (0.035 mol) was added in portions at 0 ° C to thionyl chloride (56.23 ml). The mixture was stirred at room temperature for 3 hours and the solvent was evaporated. The residue was crystallized from diethyl ether. The precipitate was filtered, washed several times with diethyl ether and recrystallized from water and DCM. The mixture was stirred for 15 hours. The precipitate was filtered and dried, giving 7.9 g (75%) of the intermediate 19.
d) Preparation of the intermediary 20
A solution of 4,4-piperidinediol hydrochloride (0.0651 mol) and potassium carbonate (0.217 mol) in DMF (250 ml) was stirred at room temperature under N 2 flow for 10 min. A solution of intermediate 19 (0.0434 moles) in DMF (50 ml) was slowly added, and the mixture was stirred at room temperature for 1 hour and then at 70 ° C for one hour. The mixture was cooled to room temperature and poured into water (1500 ml). The precipitate was filtered, washed several times with cold water and dried. The product was used in the next reaction step without further purification. A part (3 g) of the residue (13.8 g) was purified by column chromatography on silica gel (15-40 μm) (eluent: DCM / MeOH / NH 4 OH 99/1 / 0.1). The desired fractions were collected and the solvent was evaporated. The residue (2.9 g) was crystallized from MEK / DIPE, filtered and dried, giving 2.85 g of intermediate 20.
EXAMPLE A5
a) Preparing the intermediary 21
-60 ° C under N 2 flow to a mixture of 6-bromo-3-ethyl-2-methoxy-quinoline (0.043 mol) in THF (115 ml). The mixture was stirred at -60 ° C for 1 hour. A mixture of 1-cyclohexyl-3- (4-methyl-1-piperazinyl) -1-propanone, (0.043 mol) in THF (103 ml) was added dropwise at -60 ° C. The mixture was stirred at -60 ° C for 1 hour, brought to 0 ° C, emptied into a saturated NH 4 Cl solution and extracted with EtOAc. The organic layer was separated, dried (MgSO 4), filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (20-45 μm) (eluent:
DCM / MeOH / NH4OH 97/3 / 0.2 and 90/10 / 0.2). The pure fractions were collected and the solvent was evaporated, yielding 3.7 g (20%) of the intermediate 21.
b) Preparation of the intermediary 22
A mixture of intermediate 21 (0.00841 moles), tin (II) chloride (0.0336 moles) and 12N hydrochloric acid (0.121 moles) in acetic acid (36 ml) was stirred at 80 ° C for 16 hours. The mixture was emptied on ice, basified with a concentrated NH 4 OH solution and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The product was used without further purification, giving 2.45 g (74%) of intermediate 22.
EXAMPLE A6
a) Preparing the intermediary 23
Phosphoryl chloride (110.9 ml) was added dropwise at 5 ° C to DMF (81.5 ml). The mixture was stirred until complete dissolution. 4 - [(1-Oxobutyl) amino] -benzoic acid ethyl ester (0.34 mol) was added. The mixture was stirred at 100 ° C for 15 hours, then cooled to room temperature and drained in ice water. The precipitate was filtered, washed with water and dried, yielding 42.35 g (47%) of intermediate 23.
b) Preparation of the intermediary 24
A mixture of intermediate 23 (0.1606 moles) in 30% solution of sodium methanolate in MeOH (152.8 ml) and MeOH (400 ml) was stirred and refluxed for 15 hours, then cooled and poured into water with water. ice. The precipitate was filtered, washed with water and taken up in DCM. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated to dryness, giving 31.64 g (85%) of intermediate 24.
c) Preparation of the intermediary 25
Lithium aluminum-tetrahydride (0.1288 moles) was added in portions at 0 ° C under N2 flow to a solution of intermediate 24 (0.1288 moles) in THF (263 ml). The mixture was stirred for 30 min, emptied in ice water and extracted with DCM. The organic layer was separated, dried (MgSO), filtered and the solvent was evaporated to dryness, yielding 27.4 g (98%) of intermediate 25.
d) Preparation of the intermediary 26
Methansulfonyl chloride (0.104 moles) was added dropwise at 0 ° C under N2 flow to a mixture of intermediate 25 (0.069 moles) and triethylamine (0.207 moles) in DCM (120 ml). The mixture was stirred at 0 ° C for
4 hours. The solvent was evaporated to dryness (without heating). The product was used without further purification, giving 20.4 g of intermediate 26.
e) Preparing the intermediary 27
A mixture of intermediate 26 (0.0691 mol), l- (phenylmethyl) -piperazine (0.0829 mol) and potassium carbonate (0.145 mol) in acetonitrile (150 ml) was stirred and refluxed for 12 hours. The solvent was evaporated to dryness. The residue was taken up in DCM and water. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue (24.6 g) was purified by column chromatography on silica gel (20-45, μm) (eluent: DCM / MeOH / NH 4 OH 98/2 / 0.1). The pure fractions were collected and the solvent was evaporated. The residue (2.7 g) was crystallized from DIPE. The precipitate was filtered and dried, giving 1.6 g of intermediate 27, melting point 78 ° C.
EXAMPLE A7
a) Preparing the intermediary 28
NBuLi 1.6M in hexane (0.224 mol) was added at -78 ° C under N2 flow to a solution of 6-bromo-3-ethyl-2-methoxy-quinoline (0.188 mol) in THF (500 ml). The mixture was stirred at -78 ° C for 1 hour. A mixture of 3-cyclohexene-1-carboxaldehyde (0.182 mol) in THF (500 ml) was added dropwise at -78 ° C. The mixture was stirred at -78 ° C for 2 hours, then brought to 0 ° C, hydrolyzed and extracted with EtOAc. The organic layer was separated, dried (MgSO), filtered and the solvent was evaporated. The residue (58.9 g) was purified by column chromatography on silica gel (20-45 μm) (eluent: DCM / EtOAc 96/4). The pure fractions were collected and the solvent was evaporated, giving 40.5 g (72%) of the intermediate 28.
b) Preparation of the intermediary 29
A mixture of intermediate 28 (0.131 mol) in 3N hydrochloric acid (400 ml) and THF (400 ml) was stirred at 60 ° C overnight and then basified with solid potassium carbonate. The precipitate was filtered, washed with DCM and dried. The filtrate was extracted with DCM. The organic layer was separated, dried (MgSO), filtered and the solvent was evaporated. The residue was crystallized from DCM. The precipitate was filtered and dried. Part (1.5 g) of the residue (16.5 g) was taken up in MeOH. The mixture was stirred overnight. The precipitate was filtered and dried, giving 0.72 g of intermediate 29, melting point 212 ° C.
c) Preparation of the intermediary 30
Intermediate 29 (0.053 mole) was slowly added at 0 ° C to thionyl chloride (150 ml). The mixture was stirred at room temperature for 4 hours. The solvent was evaporated to dryness. The residue was collected several times in DCM. The solvent was evaporated. The product was used without further purification, giving 16 g (quant.) Of intermediate 30.
d) Preparation of the intermediary 31
A solution of 4,4-piperidinediol hydrochloride (0.079 mol) and potassium carbonate (0.265 mol) in DMF (200 ml) was stirred at room temperature under N 2 flow for 10 min. A solution of intermediate 30 (0.053 mol) in DMF (200 ml) was added slowly. The mixture was stirred at room temperature for 1 hour and then poured into water. The precipitate was filtered, washed several times with water and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue (19.2 g) was purified by column chromatography on silica gel (15-40 μm) (eluent: DCM / MeOH / NH 4 OH 96/4 / 0.2). The pure fractions were collected and the solvent was evaporated, yielding 11.4 g (59%) of the intermediate 31.
EXAMPLE A8
a) Preparing the intermediary 32
NBuLi 1.6M in hexane (0.154 mol) was added dropwise at -60 ° C under N2 flow to a mixture of 6-bromo-3-ethyl-2-methoxy-quinoline (0.118 mol) in THF (314 ml) and the mixture was stirred at -60 ° C for 1 hour. 2-thiophenecarboxaldehyde (0.142 mol) 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, emptied into a saturated NH 4 Cl solution and extracted with EtOAc. The organic layer was separated, dried (MgSO 4), filtered and the solvent was evaporated. The product was used without further purification, giving 35.37 g (quant.) Of intermediate 32.
b) Preparation of the intermediary 33
A mixture of intermediate 32 (0.118 mol) in 3N hydrochloric acid (426 ml) and THF (274 ml) was stirred at 70 ° C for 6 hours. The mixture was emptied on ice, basified with a concentrated NH 4 OH solution and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (20-45 μm) (eluent: DCM / MeOH 98/2). The pure fractions were collected and the solvent was evaporated giving 9.3 g (28%) of the intermediate 33.
c) Preparation of the intermediary 34
Intermediate 33 (0.0322 mol) was added in portions at 0 ° C to thionyl chloride (46 ml). The mixture was stirred at room temperature overnight. The solvent was evaporated to dryness. The product was used without further purification, giving 9.78 g (quant.) Of intermediate 34.
d) Preparation of the intermediate 35
Potassium carbonate (0.161 mol) was added to a mixture of 4,4-piperidinediol hydrochloride (0.0483 mol) in acetonitrile (74 ml). The mixture was stirred under N2 flow for 15 min. A mixture of intermediate 34 (0.0322 mol) in acetonitrile (98 ml) was added at room temperature. The mixture was stirred at 60 ° C overnight, then it was poured into water and extracted with DCM. The organic layer was separated, dried (MgSO4), 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 97/3 / 0.1). The pure fractions were collected and the solvent was evaporated, yielding 0.46 g (4%) of the intermediate 35.
B. Preparation of the final compounds
EXAMPLE B1 Preparation of compound 1
Sodium borohydrate (0.0318 mol) was added at 0 ° C under N2 flow to a solution of intermediate 3 (0.0245 mol) in MeOH (80 ml). The mixture was stirred for 30 min. Water (10 ml) was added. The organic solvent was evaporated. The aqueous concentrate was taken up in DCM and water and the mixture was extracted. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated to dryness. Part (3 g) of the residue (7.5 g) was crystallized from 2-propanone and a small amount of MeOH. The precipitate was filtered and dried to give 2.69 g of compound 1, melting point 172 ° C.
EXAMPLE B2 Preparation of compound 2
Potassium carbonate (0.107 mol) was added to a mixture of 4,4-piperidinediol hydrochloride (0.032 mol) in acetonitrile (49 ml). The mixture was stirred under N2 flow for 15 min. A mixture of intermediate 7 (0.0213 mol) in acetonitrile (68 ml) was added. The mixture was stirred at 60 ° C for 3 hours, then it was poured into water and extracted with DCM. The organic layer was separated, dried (MgSO4), 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 98.5 / 1.5 / 0.1). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from diethyl ether. The precipitate was filtered and dried, giving 4.16 g (51%) of compound 2, melting point 218 ° C.
EXAMPLE B3 Preparation of compound 3
X OOC
A mixture of intermediate 16 (0.002 mol) and ethyl 2-oxobutanoate (0.004 mol) in EtOH (15 ml) was stirred and refluxed for 2.5 hours, poured into water and extracted with DCM. The organic layer was separated, dried (MgSO), filtered and the solvent was evaporated. The residue (0.9 g) was purified by column chromatography on silica gel (15-40 μm) (eluent: cyclohexane / 2-propanol / NH OH 85/15/1). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from diethyl ether. The precipitate was filtered and dried, giving 0.054 g of compound 3, melting point 163 ° C.
EXAMPLE B4 Preparation of compound 4
A mixture of sodium hydride (0.42 g) in THF (10.5 ml) was stirred at room temperature for 10 min. Then, THF was decanted. DMSO (32 ml) was added, then trimethylsulfoxonium iodide (0.013 mol).
The mixture was stirred at room temperature for 1 hour. Intermediate 20 (0.0114 moles) was added slowly. The mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue was crystallized from 2-propanone / diethyl ether. The precipitate was filtered and dried. The residue was recrystallized from 2-propanone / diethyl ether. The precipitate was filtered and dried, yielding 1.54 g (36%) of compound 4, melting point 200 ° C.
EXAMPLE B5 Preparation of compound 5
A mixture of intermediate 22 (0.00623 moles) in MeOH (25 ml) was hydrogenated at room temperature under a pressure of 3 bar for 8 hours with 10% Pd / C (0.25 g) as a catalyst. After H2 (1 equiv) was collected, the catalyst was filtered through celite and the filtrate was evaporated. The residue was taken up in water and a concentrated NH 4 OH solution and the mixture was extracted with DCM. The organic layer was separated, dried (MgSO4), 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 94/6 / 0.3). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from 2-propanone. The precipitate was filtered and dried, yielding 1.07 g (43%) of compound 5, melting point 181 ° C.
EXAMPLE B6 Preparation of compound 6
NBuLi 1.6M in hexane (21.32 ml) was added dropwise at -70 ° C under N2 flow to a mixture of 1-methyl-1 H-imidazole (0.0341 mol) in THF (28 ml). The mixture was stirred at -70 ° C for 30 min. Chlorotriethylsilane (0.0341 mole) was added. The mixture was brought to room temperature. nBuLi 1.6 M in hexane (21.32 ml) was added dropwise at -70 ° C. The mixture was stirred at -70 ° C for 1 hour and then brought to -15 ° C. A mixture of intermediate 20 (0.0136 moles) in THF (50 ml) was added dropwise at -70 ° C. The mixture was allowed to warm to room temperature overnight, then it was emptied into a saturated NH 4 Cl solution and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (20-45 μm) (eluent: DCM / MeOH / NH 4 OH 94/6 / 0.5). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from 2-propanone. The precipitate was filtered and dried, yielding 5.05 g (83%) of compound 6, melting point 194 ° C.
EXAMPLE B7 Preparation of compound 7
A mixture of intermediate 27 (0.00319 mol) in 6N hydrochloric acid (70 ml) was stirred at 80 ° C for 30 min, emptied into water (50 ml) and solid potassium carbonate. The mixture was stirred for 10 min. The precipitate was filtered, rinsed with water and dried, yielding 0.9 g (78%) of compound 7, melting point 194 ° C.
EXAMPLE B8
a) Preparation of compound 8
A mixture of intermediate 19 (0.0164 mol) in 2- (dimethylamino) -ethanol (50 ml) was stirred and refluxed for 2 hours. The mixture was poured into water and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue (16 g) was purified by column chromatography on silica gel (15-40 μm) (eluent: DCM / MeOH / NH OH 94/6 / 0.5). The pure fractions were collected. The mixture was allowed to crystallize for several days (resulted in precipitation). The precipitate was filtered, taken up in petroleum ether, filtered and dried, yielding 2.8 g (48%) of compound 8, melting point 122 ° C.
b) Preparation of compound 9 v 10
compound 9 Compound 10 Compound 8 (0.02244 moles) was separated into its enantiomers by column chromatography (eluent: hexane / 2-propanol 88/12, column: CHIRALPAK AD). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from hexane and petroleum ether. The precipitate was filtered and dried, yielding 2.2 g of compound 9, melting point 115 ° C, and 2.02 g of compound 10, melting point 115 ° C.
EXAMPLE B9 Preparation of compound 11
Sodium cyanotrihydroborate (0.02 mole) was added in portions at 0 ° C under N2 flow to a solution of intermediate 31 (0.02 mole) and 2-methoxy-ethanamine (0.024 mole) in MeOH (100 ml). The mixture was stirred at room temperature for 12 hours. Water was added and the mixture was extracted with DCM. The organic layer was separated, dried (MgSO), filtered and the solvent was evaporated. The residue (9.7 g) was purified by column chromatography on silica gel (20-45 μm) (eluent: DCM / MeOH / NH4OH 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 filtered and dried to give 0.63 g of compound 11, melting point 196 ° C.
EXAMPLE B10 Preparation of compound 12
Sodium cyanotrihydroborate (0.00126 moles) at 0 ° C was added to a mixture of intermediate 35 (0.00126 moles) and 2-methoxy-ethanamine (0.00151 moles) in MeOH (10 ml). The mixture was stirred at room temperature overnight, then emptied on ice and extracted with DCM. The organic layer was separated, dried (MgSO4), 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 90/10 / 0.1). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from MEK and diethyl ether. The precipitate was filtered and dried to give 0.22 g (41%) of compound 12. Table F-1 lists the compounds that were prepared according to one of the following examples
TABLE F-1
! Pharmacological example
In vitro scintillation proximity test (SPA) for PARP-1 inhibitory activity The compounds of the present invention were tested in an in vitro test based on SPA technology (owned by Amersham Pharmacia Biotech). In principle, the test is based on well-established SPA technology for the detection of biotinylated target proteins (ADP-ribosyl), ie, histones. This ribosylation is induced using PARO-1 enzyme activated by nicked DNA and [3 H] -nicotinamide adenine dinucleotide ([3 H] -NAD +) as an ADP-ribosyl donor. As an inducer of PARP-1 enzyme activity, nicked DNA was prepared. For this, 25 mg of DNA (supplier: Sigma) was dissolved in 25 ml of DNase pH buffer (10 mM Tris-HCl, pH 7.4, 0.5 mg / ml bovine serum albumin (BSA), 5 mM MgCl2 .6H2O and 1 mM KCl) to which 50 μl of DNase solution (1 mg / ml in 0.15 M NaCl) was added. After a 90 minute incubation at 37 ° C, the reaction was terminated by adding 1.45 g of NaCl, followed by an additional incubation at 58 ° C for 15 minutes. The reaction mixture was cooled on ice and dialysed at 4 ° C for 1.5 and 2 hours respectively against 1.51 of 0.2 M KCl, and twice against 1.5 I of 0.01 M KCl for 1.5 and 2 hr respectively. The mixture was aliquoted and stored at -20 ° C. Histones (1 mg / ml, type ll-A, supplier:
Sigma) were biotinylated using the Amersham biotinylation kit and aliquots were stored at -20 ° C. A 100 mg / ml supply solution of poly (vinyltoluene) SPA spheres (PVT) (supplier: Amersham) was made 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 pH buffer (50 mM Tris / HCl, pH 8; 0.2 mM DTT; 4 mM MgCl2). A solution of 4 mM NAD + (supplier: Roche) was made in incubation pH buffer (from a 100 mM supply solution in water stored at -20 ° C). The PARP-1 enzyme was produced using known techniques, i.e. cloning and expression of the protein starting from human liver cDNA. Information regarding the protein sequence used of the enzyme PARP-1 including literature references can be found in the Swiss-Prot database under the primary access number P09874. The biotinylated histones and PVT-SPA spheres were mixed and pre-incubated for 30 minutes at room temperature. The PARP-1 enzyme (the concentration was batch dependent) was mixed with the nicked DNA and the mixture was preincubated for 30 minutes at 4 ° C. Equal parts of this solution of histones / spheres of PVT-SPA and solution of enzyme PARP-1 / DNA were mixed and 75 μl of this mixture together with 1 μl of compound in DMSO and 25 μl of [3H] -NAD + was added per Well in a 96-well microtiter plate. The final concentrations in the incubation mixture were 2 μg / ml for the biotinylated histones, 2 mg / ml for the PVT-SPA spheres, 2 μg / ml for the nicked DNA and between 5-10 μg / ml for the enzyme PARP-1. After incubation of the mixture for 15 minutes at room temperature, the reaction was terminated by adding 100 μl of 4 mM NAD + in incubation pH buffer (final concentration of 2 mM) and the plates were mixed. The spheres were allowed to settle for at least 15 minutes and plates transferred to TopCountNXT (Packard) for scintillation counting, values were expressed as counts per minute (cpm). For each experiment, controls (containing enzyme PARP-1 and DMSO without compound), an incubation of a blank (containing DMSO but not PARP-1 enzyme or compound) and samples (containing PARP-1 enzyme and compound dissolved in DMSO) were performed in parallel. All tested compounds were dissolved and finally further diluted in DMSO. First, 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"5 M and 10"8 M. In each test, the value of the blank was subtracted from the control and sample values. The control sample represented the maximum PARP-1 enzyme activity. For each sample, the amount of cpm was expressed as a percentage of the mean cpm value of the controls. When appropriate, the CI5o values (concentration of the drug, necessary to reduce the activity of PARP-1 enzyme to 50% of the control) were computerized using linear interpolation between the experimental points just above and below the 50% level. Here, the effects of test compounds are expressed as pCI5o (the negative log value of the Cl50 value). As a reference compound, 4-amino-1, 8-naphthalimide was included to validate the SPA test. The tested compounds showed inhibitory activity at the initial test concentration of 10-6 M (see Table 2).
In vitro filtration test for PARP-1 inhibitory activity The compounds of the present invention were tested in an in vitro filtration test that evaluates the activity of PARP-1 (activated in the presence of nicked DNA) by means of its pollen activity. (ADP-ribosyl) ation of histone using [32 P] -NAD as a donor of ADP-ribosyl. The radioactive ribosylated histones were precipitated by trichloroacetic acid (TCA) in 96 well filter plates and the [32 P] incorporated was measured using a scintillation counter. A mixture of histones was made (supply solution: 5 mg / ml in H2O), NAD + (supply solution: 100 mM in H2O), and [32P] -NAD + in pH buffer of incubation (50 mM Tris / HCI, pH 8; 0.2 mM DTT; 4 mM MgCl 2). PARP-1 (5-10 μg / ml) and nicked DNA were also mixed. The nicked DNA was prepared as described in the SPA in vitro for inhibitory activity of PARP-1. Seventy-five μl of the enzyme mixture PARP-1 / DNA together with 1 μl of compound in DMSO and 25 μl of histone-NAD + / [32P] -NAD + mixture was added per well of an 06-well filter plate ( 0.45 μm, supplier: Millipore). 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 nicked DNA. The plates were incubated for 15 minutes at room temperature and the reaction was terminated by the addition of 10 μl of 100% TCA cooled with ice followed by the addition of 10 μl of ice cold BSA solution (1% in H2O). The protein fraction was allowed to precipitate for 10 minutes at 4 ° C and the plates were filtered under vacuum. The plates were subsequently washed, for each well, with 1 ml of ice-cold 10% TCA, 1 ml of 5% TCA cooled with 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 ™ counter (provider: Packard) for scintillation counting and the values were expressed as counts per minute (cpm) . For each experiment, controls (containing enzyme PARP-1 and DMSO without compound), one incubation of a blank (containing DMSO but not PARP-1 enzyme or compound) and samples (containing PARP-1 enzyme and compound dissolved in DMSO) were performed in parallel. All tested compounds were dissolved and finally further diluted in DMSO. First, the compounds were tested at a concentration of 10"5 M. When the compounds showed activity at 10" 5 M, a dose response curve was made where the compounds were tested at concentrations between 10"5 M and 10"8 M. In each test, the value of the blank was subtracted from the control and sample values. The control sample represented the maximum PARP-1 enzyme activity. 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 PARP-1 enzyme activity to 50% of the control) were computed using linear interpolation between the experimental points just above and below the 50% level. Here, the effects of test compounds are expressed as pIC50 (the negative log value of the CI5o value). As a reference compound, 4-amino-1,8-naphthalimide was included to validate the filtration test. The compound compounds tested showed inhibitory activity at the initial test concentration of 10"5 M (see Table 2).
TABLE 2
The compounds can be further evaluated in a chemosensitization and / or cell radiosensitization test, a test that measures the inhibition of endogenous PARP-1 activity in cancer cell lines and finally in a radiosensitization test in vivo.
Claims (13)
1. - A compound the formula (I) the N-oxide forms, the addition salts and the stereochemical isomeric forms thereof, wherein n s 0 or 1; s is 0 or 1; X is -N = o -CR4 =, wherein R4 is hydrogen or taken together with R1 can form a bivalent radical of the formula -CH = CH-CH = CH-; And it's -N < or -CH <; Q is -NH-, -O-, -C (O) -, -CH2-CH2- or -CHR5-, wherein R5 is hydrogen, hydroxy, C6 alkyl, arylalkyl of C6-6, alkyloxycarbonyl of C? .β, C? -6-alkylamino of C? -6 or halogenoindazolyl; R1 is C6-6 alkyl or thienyl; R2 is hydrogen or taken together with R3 can form = O; R3 is hydrogen, d-6 alkyl or a radical selected from -NR6R7 (a-1), -OH (a-2), -O-R8 (a-3), -S-R9 (a-4), or - C = N (a-5), wherein R6 is -CHO, d-6 alkyl, C6-6 hydroxyalkyl, C-? 6 alkylcarbonyl. di (d.6 alkyl) aminoalkyl of C 1-6, alkylcarbonylamino of C? -6-alkyl of C? -6, piperidinylalkyl of de, piperidinylalkylaminocarbonyl of d-?, alkyloxy of d-6, alkyloxy of d-? C 1-6 alkyl, d-6 thienylalkyl, d-6 pyrrolylalkyl, C? -6 arylalkylpiperidinyl, d-β arylcarbonylalkyl, d-6 arylcarbonylpiperidinylalkyl, d-6-halogenoindoxynylpiperidinylalkyl, or C? -6 arylalkyl (d-6 alkyl) aminoalkyl of C? -6; and R7 is hydrogen or C6-alkyl; R8 is C, .6 alkyl, C? -6 alkylcarbonyl or d, 6alkyl aminoalkyl d.6 alkyl; and R9 is di (d-β) alkyl aminoalkyl of d-β; or R3 is a group of the formula - (CH2) t-Z- (b-1), where t is 0, 1 or 2; Z is a heterocyclic ring system selected from (c-1) (c-2) (c-3) (c-4) wherein each R10 independently is hydrogen, d-e alkyl, aminocarbonyl, hydroxy, - alkanediyl
C 1-6 alkyloxy-C-6 alkyl, C 1-6 alkyloxy-d-β alkylamino. di (C2-6 phenylalkenyl), piperidinylalkyl of d-β. C3-? 0 cycloalkyl, C3.6 cycloalkyl- C6-6 alkyl, aryloxy (hydroxy) C1-6alkyl, halogenoindazolyl, C6-6 arylalkyl, C2-6 arylalkenyl, morpholino, alkylimidazolyl d-ß. or C? -6 pyridinylalkylamino; each R 11 is independently hydrogen, hydroxy, piperidinyl or aryl; aryl is phenyl or phenyl substituted by halogen, d-6 alkyl or C? -6 alkyloxy; with the proviso that 6- (cyclohexyl-1H-imidazol-1-ylmethyl) -3-methyl-2 (1 H) -quinoxalinone is not included. 2. The compound according to claim 1, further characterized in that X is -N = or -CH =; R1 is C6 -6 alkyl; R3 is hydrogen, alkyl of C? -6, a radical selected from (a-1), (a-2), (a-3) or (a-4) or a group of the formula (b-1); R6 is di (C? -6-alkyl) -aminoalkyl of d-? Or C? -6-alkyloxy of d-6; R7 is hydrogen; R 8 is di (d 6 alkyl) aminoalkyl of d-β; t is 0 or 2; Z is a heterocyclic ring system selected from (c-1), (c-5), (c-6), (c-8), (c-10), (c-12) or (c-13); each R10 independently is hydrogen, d-6 alkyl, hydroxy, C? -6 alkyloxy-C? -6 alkyl, C1-6 alkyloxy-C? .6 alkylamino) morpholino, C? -6 alkylimidazolyl, or C? -6 pyridinylalkylamino; each R1 independently is hydrogen or hydroxy; and aryl is phenyl.
3. - The compound according to claim 1 and 2, further characterized in that n is 0; Q is -NH-, -CH2-CH2- or -CHR5-, wherein R5 is hydrogen, hydroxy, or arylalkyl of d-6; R1 is C1-6 alkyl; R2 is hydrogen; R3 is hydrogen, hydroxy or a group of the formula (b-1); t is 0; Z is a heterocyclic ring system selected from (c-8) or (c-13); each R 0 independently is hydrogen; and aryl is phenyl.
4. The compound according to claim 1, 2 and 3, further characterized in that the compound is selected from compound No 7, compound No 2, compound No 1 and compound No 11.
5. The compound according to any of claims 1 to 4 for use as a medicine.
6. A pharmaceutical composition comprising pharmaceutically acceptable vehicles and as an active ingredient a therapeutically effective amount of a compound as defined in claim 1 to 4.
7. A process for preparing a pharmaceutical composition as defined in claim 6, wherein the pharmaceutically acceptable carriers and a compound as defined in claim 1 to 4 are intimately mixed.
8. The use of a compound for the manufacture of a medicament for the treatment of a disorder mediated by PARP, wherein the compound is a compound of the formula (I) the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein n is 0 or 1; s is 0 or 1; X is -N = or -CR4 =, wherein R4 is hydrogen or taken together with R1 can form a bivalent radical of the formula -CH = CH-CH = CH-; And it's -N < or -CH <; Q is -NH-, -O-, -C (O) -, -CH2-CH2- or -CHR5-, wherein R5 is hydrogen, hydroxy, C? -e alkyl? arylalkyl of d-β. alkyloxycarbonyl of C? .6, C? -6-alkylamino of d-β or halogenoindazolyl; R1 is alkyl of 6 or thienyl; R2 is hydrogen or taken together with R3 can form = O; R3 is hydrogen, C6.6 alkyl or a radical selected from -NR6R7 (a-1), -OH (a-2), -O-R8 (a-3), -S-R9 (a-4) , or -C = N (a-5), wherein R6 is -CHO, C? -6 alkyl, C1-6 hydroxyalkyl. alkylcarbonyl of d-6 > di (C? -6-alkyl) aminoalkyl of C? -6, alkylcarbonylamino of d-6-alkyl of C? -e, piperidinylalkyl of C? -6, piperidinylalkylaminocarbonyl of C? -6, alkyloxy of C1-6, alkyloxy of d-6-d-β-alkyl, thienylalkyl of C6-6, pyrrolylalkyl of Ci-β, arylalkylpiperidinyl of C6, arylcarbonylalkyl of C6-6, arylcarbonylpiperidinylalkyl of d-β. halogenoindozolylpiperidinylalkyl of d-β. or d-β (C?-6) aminoalkyl d-β-arylalkyl; and R7 is hydrogen or C6 alkyl; R8 is C1-6alkyl, alkylcarbonyl of -6 or di (alkyl of d-6) aminoalkyl of C6.6; and R9 is di (C6-6 alkyl) aminoalkyl of d-β; OR R3 is a group of the formula - (CH2) t-Z- (b-1), where t is 0, 1 or 2; Z is a heterocyclic ring system selected from (c-1) (c-2) (c-3) (c-4) wherein each R) independently is hydrogen, C? -6 alkyl, aminocarbonyl, hydroxy, alkyloxy of d-β-alkyl of C-, - 6, C 1-6 alkyloxy-d-alkylamino of d-β, di (phenylalkenyl of C? -6), piperidinylalkyl of C? -6, cycloalkyl of C3.10, cycloalkylalkyl of C3-10 Ci-β alkyl, aryloxy (hydroxy) d-β alkyl, halogenoindazolyl, arylalkyl of C?-6, arylalkenyl of C2-β, morpholino, alkylimidazoyl of C?-6, or pyridinylalkylamino of C? .6; each R11 independently is hydrogen, hydroxy, piperidinyl or aryl; the aryl is phenyl or phenyl substituted with halogen, Ci-β alkyl or d-β- 9 alkyloxy- The use claimed in claim 8 of a PARP inhibitor of the formula (I) for the manufacture of a medication for the treatment of a disorder mediated by PARP-1. 10. The use claimed in claims 8 and 9 wherein the treatment involves chemosensitization. 11. The use claimed in claims 8 and 9 wherein the treatment involves radiosensitization. 12. A combination of a compound with a chemotherapeutic agent wherein the compound is a compound of the formula (I) the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein n is 0 or 1; s is 0 or 1; X is -N = or -CR4 =, wherein R4 is hydrogen or taken together with R1 can form a bivalent radical of the formula -CH = CH-CH = CH-; And it's -N < or -CH <; Q is -NH-, -O-, -C (O) -, -CH2-CH2- or -CHR5-, wherein R5 is hydrogen, hydroxy, d-6 alkyl, arylalkyl of C? .6, alkyloxycarbonyl of d-6, d-6-alkylamino of d.6 or halogenoindazolyl; R1 is d-6 alkyl or thienyl; R2 is hydrogen or taken together with R3 can form = O; R3 is hydrogen, d-β alkyl or a radical selected from -NR6R7 (a-1), -OH (a-2), -O-R8 (a-3), -S-R9 (a-4), or -C = N (a-5), wherein R6 is -CHO, d-β alkyl, d-β hydroxyalkyl, C?-6 alkylcarbonyl, di (C?-6) alkyl aminoalkyl of d- 6, C 1 .6 alkylcarbonylamino-C 1-6 alkyl, piperidinylalkyl of d-β. piperidinylalkylaminocarbonyl of C? .6, alkyloxy of C? _6, alkyloxy of d-β-alkyl of C? -6, thienylalkyl of d.6, pyrrolylalkyl of d-?, arylalkylpiperidinyl of C1-6, arylcarbonylalkyl of C? -6 , arylcarbonylpiperidinylalkyl of C? .6, halogenoindozolylpiperidinylalkyl of C? -6, or arylalkyl of d-? (C? -6 alkyl) -alkyl? -6alkyl; and R7 is hydrogen or C? -β alkyl; R8 is d-β alkyl, d-β alkyl or di (d6 alkyl) aminoalkyl of d.6; and R9 is di (C6-alkyl) aminoalkyl of C6-6; or R3 is a group of the formula - (CH2) t-Z- (b-1), where t is 0, 1 or 2; Z is a heterocyclic ring system selected from (c-1) (c-2) (c-3) (c-4) wherein each R10 independently is hydrogen, C? -6 alkyl, aminocarbonyl, hydroxy, alkyloxy of d-6-alkyl of d-6, alkyloxy of Ci-β-alkylamino of d-β, di (phenylalkenyl of d-6), piperidinylalkyl of d-β, cycloalkyl of C3.10, cycloalkylalkyl of C3.10 C 1-6 alkyl, aryloxy (hydroxy) d-6 alkyl, halogenoindazolyl, arylalkyl of C 1-6, arylalkenyl of C 2-6, morpholino, alkylimidazolyl of C 1-6, or pyridinylalkylamino of d-β; each R11 independently is hydrogen, hydroxy, piperidinyl or aryl; the aryl is phenyl or phenyl substituted by halogen, d-β alkyl or d-6 alkyloxy. 13. A method for preparing a compound as defined in claim 1, said method being characterized in that it comprises a) hydrolysis of intermediates of the formula (HIV), in accordance with methods known in the art, by subjecting the intermediates of the formula (VIII) to appropriate reagents, such as tin chloride, acetic acid and hydrochloric acid, in the presence of a solvent inert to the reaction, e.g. tetrahydrofuran. (D b) cyclization of intermediates of the formula (X), in accordance with cyclization procedures known in the art to compounds of the formula (1) wherein X is CH herein referred to as compounds of the formula (Ij), preferably in the presence of a suitable Lewis acid, e.g., aluminum chloride either in net form or in a suitable solvent such as, for example, an aromatic hydrocarbon, e.g., benzene, chlorobenzene, methylbenzene and the like; halogenated hydrocarbons, v.gr. trichloromethane, tetrachloromethane and the like; an ether, e.g., tetrahydrofuran, 1,4-dioxane and the like or mixtures of said solvents. c) the condensation of an appropriate ortho-benzenediamine of the formula (XI) with an ester of the formula (XII) to compounds of the formula (1), wherein X is N and R2 taken together with R3 form = O, here referred to as compounds of the formula (la-1), in the presence of a carboxylic acid, e.g., 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.
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