MXPA01000393A - Pharmaceutical compositions comprising 2-quinolones - Google Patents

Abstract

The invention concerns a pharmaceutical composition having an activity on the proliferation of clonogenic cells in tumours and comprising an efficient amount of a compound selected among the compounds of formulae (I) and (Ia) wherein:X, R1, R2, R3, R4, R5, R6 are as defined in Claim 1.

Description

PHARMACEUTICAL COMPOSITIONS COMPRISING 2- QUINOLONES The present invention concerns pharmaceutical compositions comprising 2-quinolones or derivative compounds.

EP-A-0 024 638 already describes the use of certain 2-quinolones in therapeutics to increase the synthesis of glucose. O-A-93/11115 describes the use of 2-quinolones, essentially in substitution 7-chloro as antagonists of the -SIMA receptors. In addition, O-A-94/02145 describes the use of 2-aryl-4-quinolones as anti-tumor agents.

A cancer is a disorder of the somatic genes in the course of which the disturbances in genetic functioning are amplified as the tumor process progresses from the state of precancerous lesion to that of malignant transformation, the cancerous tumor becomes metastatic and continues to be resistant to the cytotoxic drugs.

Despite the very important efforts carried out in all the developed countries, in particular through Ref.126138 experimental and clinical research programs, mortality due to different cancers (solid tumors and hematological malignancies) remains unacceptably high. In many countries, cancer mortality is in the second row, immediately after cardio-vascular diseases.

In terms of newly diagnosed cancers, the distribution between solid tumors and hematological malignancies (bone marrow, blood, lymphatic system) shows that 9 cancers out of 10 are solid tumors. Contrary to what is observed in hematologic oncology (therapeutic achievements in 40 to 90% of blood cell cancers), only a small number of advanced or disseminated solid tumors respond only to chemotherapeutic treatments. It is partly for this reason that global cancer mortality has grown in the United States between 1973 and 1992.

Unfortunately, it is not certain that this trend can be reversed only by the appearance, together with the established chemotherapeutic arsenal, of new anti-tumor drugs such as taxanes (paclitaxel and docetaxel) that interfere with the formation of microtubules (WP Mc Guire et al. Am. Intern. Med., 1989), topoisomerase I inhibitors derived from camptothecin (topotecan and irinotecan), vinorelbine (new alkaloid from maiden grass), gemcitabine (new antimetabolic cytotoxic), raltitrexide (inhibitor of thymidylase synthetase) and miltefosine (first representative of the family of alkyl-lysophospholipids). These treatments are added, either in the first attempt, or in the second attempt, to the drugs whose specific activity is currently well recognized as doxorubicin, cisplatin, vincristine, methotrexate, 5-fluorouration.

One of the most difficult current problems of anticancer chemotherapy is due to the fact that numerous populations of malignant cells present an important resistance to the established cytotoxic substances. Continuously this situation results from the existence of multiple resistance genes or the frequency of genetic mutations in certain types of tumors. Thus, the treatment of cancers requires new attempts, complementary to those currently applied, and aimed at better combating the extension and heterogeneity of the tumor burden and the acquisition of resistance to "multiple cytotoxic drugs".

Among these new attempts, some are already promising. This is the case of the induction of apoptosis, the inhibition of the tumor agglomerate and metastatic processes without talking about gene therapy or immunotherapy.

The inventors were interested in a different attempt.

The objective investigated was to make the population of tumor cells more sensitive to the anticancer treatments of reference in order to achieve a double benefit: 1) increase the cytotoxic activity and consequently the efficiency and 2) decrease the frequency and severity of certain side effects thanks to the reduction of the posology that could follow the induction of increased anti-tumor efficiency.

It is this strategy that is the origin of the discovery of compositions capable of inducing a very significant increase in the cytotoxic activity of approved anticancer drugs. These compositions have the ability either to stimulate the recruitment of clonogenic cells into the tumor making it more sensitive to conventional treatment by cytotoxic agents, or to inhibit the proliferation of clonogenic cells, which contribute to tumor regression.

The subject of the present invention is also the use, in the treatment of cancers with at least one antitumor selected from cytotoxic agents, of a compound having an activity on the proliferation of clonogenic cells in tumors, selected from the compounds of formula . in which: X is selected from = 0, = S and = N-NH-R7, R7 is a phenyl or pyridyl group, R1, R2, R3 and R4 are independently selected from H, OH, an alkyl group at C? -C4, an alkoxy group in C? -C4, a group -OCO-R8, R8 an alkyl group in C? ~ C4, and a group derived from a soda, at least one of the substituents R1, R ", R3, or R4 being different from H, and R2 and R3 can together form a methylenedioxy group.

R5 is a phenyl group or a 1 to 3 phenyl group substituted by groups selected from H, OH, an alkoxy group in C? -C, a group -OCOR6, a phenyl group (alkoxy in C? -C4), a group - 0-S02-R'8, R '8 is an alkyl group in C? -C4 or a CF group and a group derived from a osa.

RD is selected from H, an alkyl group at C? -C4, a group -CO-R9 and a group -A-R10, R6a is selected from an alkyl group at C? ~ C4, a group -CO-R9 and a group -A-R10, R9 is an alkyl group in C? -C4, A is an alkylene group in C? ~ C4.

Rlü is selected from the heterocyclic groups of or 6 links having 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, the CN group, a group -COOR11, -CONR1A13, a group -NR14R15, and a group-COR16, R11, R12, R13, R14, R15 and R16 are independently selected from a hydrogen atom, a C en-C4 alkyl group and a phenyl (C-C4 alkyl) group, R4 and R6 which can also together form a group -CO-CH2-CH2-, The cytotoxic agents can be used in their usual dose and, in this case, their efficiency is improved, or in milder doses taking into account the increase of their antitumor efficiency.

In a preferred embodiment, a compound of formula (I) is used in which: - R1 is an alkoxy group in C? -C4 - R- is a hydrogen atom - RJ is an alkoxy group in C? ~ C4 - R4 is a hydrogen atom, and in particular a compound of formula (I) in which - R5 is a group 4- (C1-C4 alkoxy) phenyl, and very particularly a compound of formula (I) in which: - R1 is a methoxy group, - RJ is a methoxy group, and - R5 is a 4-methoxyphenyl group.

It has also been discovered that at least certain compounds of formula (I) had anti-tumor activity by themselves.

The present invention also relates to a composition having an activity on the proliferation of clonogenic cells in tumors that interferes with the degeneration of clonogenic cells, either by stimulation of proliferation and recruitment, or by inhibition of proliferation, and comprising an efficient amount of a compound of formula: in which X is selected from = 0, = S and = N-NH-R7, R7 is a phenyl or pyridyl group, R1, R2, R3 and R4 are independently selected from each other from H, OH, an alkyl group at C? C4, an alkoxy group in C? -C4, an -OCO-R8 group, where R8 is an alkyl group in Ci-C4, and a group derived from a osa, at least one of the substituents R1, R, R3 or R4, they are different from H, and R2 and R3 that can together form a methylenedioxy group, R5 is a phenyl group or a phenyl group 1 to 3 times substituted by groups selected from H, OH, an alkoxy group at C? -C4, a group -OCOR8, a phenyl group (alkoxy at C? -C4), a group -0-S02-R'8, where R 'b is an alkyl group in C? -C4 or a CFJ group and a group derived from a bear.

R5 is selected from H, an alkyl group at C? -C4, a group -CO-R9 and a group -A-R10, R6a is selected from, a group -CO-R9, and a group -A-R10, being R9 is an alkyl group in C? -C4, where A is an alkylene group in C1-C4, where R? 0 is selected from heterocyclic groups of 5 or 6 links having 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen , the CN group, a group-COOR11, -CONR12R13, a group -NR14R15, and a group -COR16, R11, R12, R13, R14, R15 and R16 which are independently selected from a hydrogen atom, an alkyl group at Cx-C4 and a phenyl group (alkyl at C? ~ C), R4 and Rd which can also together form a group -CO-CH2-CH2-.

The subject of the present invention is also novel compounds, namely compounds of the formula: in which X is selected from = 0, = S and = N-NH-R7, where R7 is a phenyl or pyridyl group, R1, R2, RJ and R4 are independently selected from each other between H, OH, an alkyl group at C? -C4, an alkoxy group at C? -C, an -OCO-R8 group, where R8 is an alkyl group at C? ~ C, and a group derived from a bear, at least one of its substituents R1, R2, R3 or R4 which is different from H and R2 and R3 which can together form a methylenedioxy group, R5 is a phenyl group or a phenyl group 1 to 3 times substituted by groups selected from H, OH, an alkoxy group at C? -C4, a group -OCOR8, a phenyl group (alkoxy at C? -C4), a group -0-S02-R'8, where R '8 is an alkyl group in C? -C4 or a CFJ group, is a group derived from a bear, R6 is selected from H, an alkyl group in C? -C4, a group -CO-R and a group -A-R10, R6a is selected from a group -CO-R9, and a group -A-R1C, where RQ is an alkyl group in C? -C4, where A is an alkyl group in C? ~ C4,.

R10 which is selected from the 5- or 6-membered heterocyclic groups having 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, the CN group, a group -COOR11, -C0NR12R13, a group -NR14R15, and a group -COR16, R11, R12, R13, R14, R15 and R16 which are independently selected from a hydrogen atom, an alkyl group at C? -C4 and a phenyl group (alkyl at C? -C4), R4 and R6 which can also together form a group -CO-CH2-CH2-, excluding compounds in which X = 0, R6 = H and two of the substituents R1, R2, R3, R4 are OH or OCH3 .

In the chemotherapeutic treatment of cancers by cytotoxic agents, the compounds of formula (I) and la) can be administered at the beginning of chemotherapeutic treatments either once or for several days at the beginning of these treatments (for example during 5 to 7 days) and, depending on the chemotherapeutic protocol, at the beginning of each treatment cycle (for example, 2 to 5 days) during the course of each treatment.

The compounds of formula (I) and (Ia) are advantageously administered by perfusion (generally in 1 to 3 hours) in doses of 5 to 50 mg / kg / day or 200 to 2000 mg / m2 / day.

In order to obtain a maximum effect on the production (inhibition or stimulation) of clonogenic cells, the compounds of formula (I) and (Ia) should be administered in such a way that the tissue concentrations obtained are the highest that can be contemplated.

For the treatment protocols in the acute phases of the cures, the intravenous route is in privilege using: - perfusion syringes ready for use (sacks, bottles ...) intended to be administered as such by intravenous infusion with the help of an infusion line and according to the recommended flow: lyophilized to be put into solution for intravenous infusion with the help of pharmaceutical solutes known to the person skilled in the art; for maintenance treatments, it is also possible to contemplate the oral route when the treatment of chemotherapy is preferred over the administration of cytotoxic orally. For this purpose, tablets (for oral or perlingual absorption), tablets for instant or prolonged release, oral solutions, suspensions, granules, capsules ... may be used.

The cytotoxic agents can be selected from: (i) intercalating agents, particularly doxorubicin (Adramycin), danorubicin, epirubicin, idarubicin, zorubicin, aclarubicin, pirubicin, acridine, mitoxantrone, actinomycin D, epitilinium acetate; ii) alkylating agents selected from the platinum derivatives (cisplatin, carboplatin, oxaplatinum); iii) a compound selected from the other groups of alkylating agents; - cyclophosphamide, ifosfamide, chlormethrin, melphalan, chlorambucil, estramustine, - busulfan, mitomycin C, - nitroureas: BOCNU (carmustine), CCNU (lamustine), fotemustine, streptosotocin, - triacenes or derivatives: procarbazine, descarbazine, - pipobroman, - ethylene imines: altretamine, triethylene-thiophosphoramide, iv) a compound selected from the other groups of anti-metabolic agents: - antifolic: methotrexate, raltitrexed, antipyrimidics: 5-fluorouracil (5FU), cytarabine (Ara-C), - hydroxylurea, antipuric_purinetol, thioguanine, pentostatin, cladribine - inducers of cytotoxic nucleoside synthesis: gemcitabine, v) a compound selected from the other groups of tuber-like agents; - vinca-alkaloids that disorganize the miotic spindle: vincristine, vinblastine, vindesine, navelbine - agents that block the depolymerization of the miotic spindle: paclitaxel, docetaxel, - agents that induce DNA breaks by inhibition of topoisomerase II: etoposide, teniposide - inhibitors of topoisomerase I that induces DNA cuts: topotecan, irinotecan, vi) an agent that cleaves, fragments DNA, such as bleomycin, vii) one of the following compounds; plicamycin, L-asparginase, mitoguazone, dacarbazine, viii) an anticancer progenitor steroid: medroxy-progesterone, megestrol, ix) an anti-cancer estrogen steroid: diethylstibestrol; tetrasodium fosfestrol, x) an anti-estrogen: tamoxifen, droloxifene, raloxifene, amino-glutethimide, xi) a steroidal anti-androgen (ex cyproterone) or a non-steroidal anti-androgen (flutamide, nilutamide).

In particular, the compounds of formula (I) and (la) may be associated with all treatments by the major cytotoxic agents used in polychemotherapies of solid tumors such as: - doxorubicin - the alkylating agents: oxaphorins, (cyclophosphamide, ifosfamide, chlorambucil, melphalan) - the nitrosoureas - mitomycin - anti-metabolites such as methotrexate, 5-FU, Ara-C, capecitabine - agents that interfere with tubulin: vinca alkaloids (vincrisine, vinblastine, vindesine, navelbine), toxoids (pacitaxel, docetaxel), derivatives of epipodophyllotoxins (etoposide, teniposide) - bleomycin - inhibitors of topoisomerase I: topotecan, irinotecan, Likewise, the compounds of formula (I) and (la) may be associated with treatments by the major cytotoxic agents used in oncohematology for the treatment of cancers in the blood: Hodgkin's disease: cyclophosphamide, mechlorethamine, chlorambucil, melphalan, ifosfamide, 10 etoposide, doxorubicin, daunorubicin; acute leukemias: methotrexate, 6-mercaptopurine, cytarabine, vinblastine, vincristine, doxorubicin, daunorubicin, L-asparginase, 15 - non-Hodgkin's malignant lymphomas: mechlorethamine, chlorambucil, cyclophosphamide, melphalan, ifosfamide, methotrexate, cytarabine, vinblastine,, vincristine, etoposide , doxorubicin, daunorubicin, carmustine, lomustine, cisplastin; chronic lymphoid leukemia: mechlorethamine, chlorambucil, cyclophosphamide, melphalan, ifosfamide.

In a general manner, the compounds of formula (I) they can be prepared according to the following reaction schemes. SCHEME I SCHEME II As the alkylating reagent, a reagent of type XR ° wherein X = I, Br, Cl.

To vary, a compound CH = CH-R can be used to fix a group RD = -CH: -CH2-R (corresponding to the group -A-R10 defined above).

SCHEME III SCHEME IV R? In addition, it is possible to convert part or all of the alkoxy groups to hydroxy groups according to known methods. Also the groups, hydroxy can be transformed into ester or sulfonate according to the known methods.

Likewise, it is possible to convert according to known methods a group -A-COOR11 in which R11 is an alkyl or phenylalkyl group in an -A-COOH group and convert an -A-COOH group to an -A-CONR12R13 group.

The compounds in which R4 and Rd form a group -CO-CH; -CH2- can be obtained by cyclization of a compound in which R4 = H and R6 = -CH: -CH: -COOH.

EXAMPLE 1: 5, 7-dimethoxy-3- (4-methoxyphenyl) -1-, 2-dihydro-2-quinoline ketone (Compound 1) a) N- (3,5-dimethoxyphenyl) -2- (4-methoxyphenyl) acetamide (compound 2) Under nitrogen atmosphere, 500 mg (3.3 mmoles) of 3,5-dimethoxyaniline was solubilized in toluene (7 ml) at 0 ° C. A solution of 4-methoxyphenhexyl chloride (0.5 ml, 3.3 miryols) in 5 ml of toluene was added dropwise to the medium. The reaction mixture was stirred at room temperature for 1 hour, then the medium was hydrolyzed by a cold solution of sodium bicarbonate. The biphasic system was stirred vigorously for 30 minutes, then the organic phase was collected. The aqueous phase was extracted with ethyl acetate (twice). The organic phase was dried over MgSO4, then evaporated. The residue obtained was crystallized from petroleum ether to yield 810 mg (82%) of compound 2.

.PF 135-137 ° C (toluene) .IR (KBr) n 3292, 1658, 1625 cm "1 .A-NMR (250 MHz, CDC13): d 3.66 (s, 2H, CH2), s, 6H, OCH3), 3.82 (s, 3H, OCH3), 6.20 (t, ÍH, J = 2.2 Hz, HAr), 6. 26-6.66 (m, 2H, HAr), 6.95 (d, 2H, J = 7.5 Hz, HAr), 6.97 (broad s, HI, NH), 7.23 (d, 2H, J = 7.5 Hz, HAr). .13C NMR (62.90 MHz, CDC13): d 44.0, 55.3, 55.4 (2), 96.7, 97.9 (2), 114.4 (2), 126.2, 130.7 (2), 139.4, 159.0, 161.0 (2), 169.5.

.SM (ion spray): 302 (M + l) t b) 2-Chloro-5,7-dimethoxy-3- (4-methoxyphenyl) -1,2-dihydroquinoline (Compound 3) Under nitrogen atmosphere and at -30 ° C, 0.31 ml (4.0 mmol, 1.5 eq) of N, N-dimethylformamide was added dropwise to 1.75 ml (20.0 mmol, 7.5 eq) of P0C13. the medium was stirred for 15 min at -30 ° C, then 810 mg of amide 2 (2.7 mmol) was added. It was brought to room temperature, with stirring then the reaction was heated at 75 ° C for 2.5 hours. At the end of the reaction, this solution was poured onto stacked ice, neutralized with a 30% ammonia solution, then extracted with dichloromethane. The organic phase was dried over MgSO4 then evaporated. The residue obtained was purified by chromatography on a silica column (eluent: AcOEt / EP 3: 7) to give 270 mg (30%) of compound 3. P-f-156-157A (toluene) ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^ A NMR (250 MHz, CDC13): d 3.87 (s, 3H, OCH3), 3.93 (s, 3H, OCH3), 3.95 (s, 3H, OCH5), 6.52 ( d, 1 H, J = 2.0 Hz, HAr), 6.97-7.01 (m, 3H, HAr), 6.95 (d, 2H, J = 8.7 Hz, HAr), 8.35 (s, ÍH, HAr). 13C NMR (62.9 MHz, CDC13): d 55.3, 55.7, 55.8, 98.6, 98.9, 113.6 (2), 115.8, 125.9, 130.5, 131.0 (2), 133.8, 149.0, 150.5, 156.0, 159.4, 162.1. c) 5, 7-dimethoxy -3- (4-methoxy-phenyl) -1,2-dihydroxy-2-quinoline ketone (Compound 1) Compound 3 (250 mg, 0.76 mmol) in acetic acid solution (1.2 ml, 26.25 mmol per mmol of 3) and water (0.04 ml, 2.77 mmol per mmol of 3) was stirred at reflux for 3 hours. The acetic acid was evaporated. The residue was taken again in water, neutralized with a 25% sodium hydroxide solution, to be finally extracted with dichloromethane. The organic phase was dried over MgSO 4, then evaporated under reduced pressure. The residue was taken again in ethyl acetate, this operation involved the crystallization of the final product. The crystals thus obtained were filtered to give 200 mg (85%) of compound 1.

The overall yield of the synthesis applied to obtain compound 1 is 21%.

.PF 254-255 ° C (AcOEt) IR (KBr) n 1664, 1628, 1573, 1518 c -i NMR (250 MHz, DMSO-d6): d 3.78 (s, 3H, OCH3), 3.81 (s, 3H, OCH3), 3.89 (s, 3H, 0CH3), 6.35 (d, ÍH, J = 2.0 Hz, HAr). 6.45 (d, 1 H, J = 2.0 Hz, HAl), 6.95 (d, 2H, J = 7.5 Hz, HAr), 7.66 (d, 2H, J = 7.5 Hz, HAr), 7.96 (s, 1 H, HAr), 11.76 (broad s, ÍH, NH). 1JC NMR (62.90 MHz, (DMSO-d6): d 55.1, 55.4, 55.9, 90.0, 93.0, 104.6, 113.3 (2), 126.5, 129.0, 129.6 (2), 130.2, 140.5, 156.6, 158.7, 161.5 161.9.

.SM (ion spray): m / z 312 M + l) Analysis calculated for C? 8H? 7N04: C, 69.44; H, 5.50; N, 4.50, found: C, 69.29; H, 5.40; N, 4.55.

EXAMPLE 5, 7-dimethoxy-3- (4-hydroxyphenyl) -1,2-dihydro-2-quinoline ketone (Compound 4) Under an inert atmosphere, 530 mg (1.70 mmol) of compound 1 was solubilized in 15 ml of acetic acid. A commercial solution of 48% HBr in water (2.65 ml) (exothermic reaction) is added dropwise to the reaction mixture. The final solution is refluxed with stirring for 5 h. After cooling, the reaction is diluted by the addition of water, then neutralized with a 10% sodium solution (pH = 6-7). The product is extracted with dichloromethane (twice). The organic phase is dried over MgSO, then evaporated under reduced pressure. The residue is purified by chromatography on a silica column (eluent CH: Cl- / MeOH 9: 1) to give 175 mg (35%) of compound 4.

.PF 275-276 ° C (AcOEt) IR (KBr) n 1628, 1604, 1558, 1518 cm "A NMR (250 MHz, DMSO-d6): d 3.80 (s, 3H, OCH3), 3.89 (s, 3H, OCH3), 6.35 (d, ÍH, J = 2.5 Hz, HAr), 6.43 (d, ÍH, J = 2.5 Hz, HAr), 6.78 (d, 2H, J = 7.5 Hz, HAr), 7.55 (d, 2H, J = 7.5 Hz, HAr), 7.92 (s, ÍH, HAr), 9.48 (s, 1H, OH), 11.72 (s broad, ÍH. NH). 13 C NMR (62.90 MHz, DMSO-d 6): d 55.4, 55.9, 90.0, 93.0, 104.7, 114.8 (2), 126.9, 127.4, 129.6, 129.8 (2), 140.4, 156.6, 156.9, 161.6, 161.8.

.SM (ion spray): m / z 298 (M + l) + Analysis calculated for C? 7H? 5N0: C, 68.68; H, 5.09; N, 4.71. Found: C, 68.90; H, 5.09; N, 4.90.

EXAMPLE 3: 5, 7-Dihydroxy-3- (4-hydroxyphenyl) -1,2-dihydro-2-quinoline ketone (Compound 5) (CRL8311) Under an inert atmosphere, 1.0 g (3.2 mmol) of compound 1 was dissolved in 15 ml of acetic acid. A commercial solution of 48% HBr in water is added dropwise (5 ml) (exothermic reaction) to the reaction mixture. The final solution was stirred at reflux for 3 days. After cooling, the reaction was diluted by the addition of water, then neutralized with a 10% sodium hydroxide solution (pH = 6-7). The product was extracted with dichloromethane (twice) . The organic phase was dried over MgSO 4, then evaporated under reduced pressure. The residue obtained was purified by chromatography on a column of silica (eluent CH2Cl2 / MeOH 9: 1) to give 320 mg (37%) of compound 5.

PF > 280 ° C A NMR (250 MHz, DMSO) -d6): d 6.11 (d, ÍH, J = 2.0 Hz, HAr), 6.18 (d, ÍH, J = 2.0 Hz, HAr), 6.76 (d, 2H, J = 8.6 Hz, HAr), 7.52 (d, 2H, J = 8.6 Hz, HAr), 7.89 (s, ÍH, HAr), 9. 42 (s, ÍH, OH), 9.84 (s, ÍH, OH), 10.21 (s, ÍH, OH), 11.46 (broad s, ÍH, NH). 13 C NMR (62.90 MHz, DMSO-d 6): d 91.3, 96.4, 103.5, 114.7 (2), 125.1, 127.8, 129.4 (2), 130.4, 140.7, 155.3, 156.6, 160.1, 161.8.

.SM (ion spray): m / z 270 (M + l) "" Analysis calculated for C? 5HnN04: C, 66.91; H, 4.12; N, 5.20. Found: C, 66.80; H, 4.00; N, 5.40.

EXAMPLE 4: 5, 7-Dimethoxy-3- (methoxy-enyl) -1,2-dihydro-2-quinolintio-ketone (Compound 6) Under an inert atmosphere, 100 mg (0.32 mmol) of compound 1 was solubilized in 15 ml of toluene (hot solution), 260 mg (0.64 mmo], 2 eq) of Lawesson's reagent were added to the reaction mixture. The final solution was stirred at reflux for 18 h. After cooling, the toluene was evaporated. The residue obtained was purified by chromatography on a silica column (eluent CH2Cl2 / AcOEt 9: 1) to give 81 mg (77%) of compound 6.

.PF 229-230 ° C (Et20) .IR (KBr) 1636, 1610, 1524 cm-1 -. *. ** 3 & amp; .F. faw > - ^ - - -%. < % * a ,, - ¿i * a ^ fe - ^^ -? NMR (250 MHz, DMSO-d6): d 3.78 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 3.89 (s, 3H, OCH3), 6.49 (d, ÍH, J = 1.9 Hz, HAr), 6.79 (d, ÍH, J = 1.9 Hz, HAr), 6.92 (d, 2H, J = 8.7 Hz, HAr), 7.49 (d, 2H, J = 8.7 Hz, HAr), 7.78 (s, ÍH , HAr), 13. 50 (s broad, ÍH, NH). 13 C NMR (62.90 MHz, CDCl 3): d 65.1, 55.6, 56.1, 90.2, 95.2, 108.9, 112.9 (2). 128.2, 130.7 (2), 132.0, 136.3, 140.9, 156.4, 158.5, 162.5, 180.5.

.SM (ion spray): m / z 328 (M + l) + Calculated analysis for C18H? 7N03S: C, 66.03; H, 5.23; N, 4.28. Found: C, 66.30; H, 5.30; N, 4.35.

EXAMPLE 5: 5, 7-dimethoxy-3- (4-methoxyphenyl) -1-methyl-1,2-dihydro-2-quinoline ketone (Compound 7) Under nitrogen atmosphere, 600 mg (1.93 mmoles) of compound 1 was solubilized in 30 ml of anhydrous N, N-dimethylformamide (DMF). At 0 ° C, 93 mg (3.86 mmol, 2 eq) of NaOH, previously washed with petroleum ether, were added in small portions to the reaction solution (exothermic reaction). A solution of methyl iodide (0.48 ml, 7.72 mmol, 4 eq.) Diluted in 5 ml of DMF was added to the medium. The reaction is heated for 18 h at 90 ° C. After cooling, the water was poured into the reaction mixture, then the solution was stirred for 15 minutes. The solid obtained was collected by filtration on glass fiber then rinsed with water. The solid was dissolved in CH2Cl2 and washed twice with water. The organic phase obtained was dried over magnesium sulfate, then evaporated under reduced pressure. The residue obtained was purified by chromatography on a silica column (C ^ C AcOEt 8: 2) to give 408 mg (68%) of compound 7 and 157 mg (25%) of derivative 7a.

Compound 7: .PF 125 ° C (AcOEt / EP) IR (KBr) n 1635, 1596, 1590, 1514 cm '-1 A NMR (250 MHz, CDC13): d 3.73 (s, 3H, NCH3), 3.83 (s, 3H, OCH3), 3.91 (s, 6H, OCH3), 6.30 (d, ÍH, J = 2.0 Hz, HAr), 6.37 (d, ÍH, J = 2.0 Hz, HAr), 6.94 (d, 2H, J = 7.5 Hz, HAr), 7.67 (d, 2H , J = 7.5 Hz, HAr), 8.12 (s, ÍH, H,,,). 13C NMR (62.90 MHz, CDC13): d 30.3, 55.3, 55.5, 55.8, 90.2, 92.6, 106.1, 113.5 (2), 127.0, 130.0, 130.1 (2), 130.2, 141.7, 157.6, 159.1, 162.2 (2) .

.SM (ion spray): m / z 326 (M + l) + Analysis calculated for C? 9H? 9N04: C, 70.14; H, 5.89; N, 4.30. Found: C, 70.00; H, 5.73; N, 4.24.

Compound 7a: 2,5, 7 -trime toxi -3- (4-methoxyphenyl) quinoline .PF 106-107 ° C (AcOEt / EP) IR (KBr) n 1621, 1515, 1265 cm '-1 A PMN (250 MHz, CDC13): d 3.86 (s, 3H, OCH3), 3.94 (s, 6H , OCH3), 4.08 (s, 3H, OCH3), 6.40 (d, ÍH, J = 1.8 Hz, HAr), 6.85 (d, ÍH, J = 1.8 Hz, HAr), 6.97 (d, 2H, J = 8.8 Hz, HAr), 7.57 (d, 2H, J = 8.8 Hz, HAr), 8.26 (s, 1 H, HAr). 13 C NMR (62.90 MHz, CDC13): d 53.5, 65.3, 55.5, 55.6, 95.9, 98.5, 112.8, 113.6 (2), 122.1, 129.6, 130.5 (2), 132.3, 147.9, 156.3, 158.9, 160.6, 161.3.

.SM (ion spray): m / z 326 (M + l) + Analysis calculated for C? 9H? 9N04: C, 70.14; H, 5.89; N, 4.30. Found: C, 69.89; H, 5.81; N, 4.10.

EXAMPLE 6: 5, 7-dimethoxy-3- (4-hydroxy-phenyl) -1-methyl-1,2-dihydro-2-quinoline ketone (Compound 8) Under an inert atmosphere, 408 mg (1.3 mmol) of compound 7 were dissolved in 15 ml of acetic acid. A commercial solution of 48% HBr in water (2 ml) (exothermic reaction) was added dropwise to the reaction mixture.

The final solution was stirred at reflux for 5 h. After cooling, the reaction was diluted by the addition of water, then neutralized with a 10% sodium hydroxide solution (pH = 6-7). The product was extracted with dichloromethane (twice) . The organic phase was dried over MgSO 4, then evaporated under reduced pressure. The residue obtained was purified by chromatography on a silica column (eluent CH2Cl2 / AcOEt 7: 3) to give 220 mg (56%) of compound 8.

.PF 204-205 ° C (AcOEt) At NMR (250 MHz, (DMSO-d6): d 3.63 (s, 3H, NCH3), 3.89 (s, 3H, OCH3), 3.90 (s, 3H, OCH3), 6.46 (d, ÍH, J = 1.9 Hz, HAr), 6.54 (d, ÍH, J = 1.9 Hz, HAr), 6.76 (d, 2H, J = 8.5 Hz, HAr), 7.48 (d, 2H, J = 8.5 Hz, HAr), 7.93 (s, ÍH, HAr), 9. 47 (s, ÍH, OH). 13 C NMR (62.90 MHz, DMSO-d 6): d 30.5, 56.1, 56.5, 91.3, 93.4, 105.3, 115.2 (2), 126.5, 128.4, 129.2, 130.2 (2), 141.7, 157.4 (2), 161.4, 162.5 .

.SM: m / z 312 (M + l) +. Analysis calculated for C? 8H? 7N04: C, 69.44; H, 5.50; N, 4.50. Found: C, 69.65; H, 5.59; N, 4.60.

EXAMPLE 7: 5, 7-Dihydroxy-3- (4-hydroxyphenyl) -1-methyl-1,2-dihydro-2-quinoline ketone (Compound 9) 1. Method A: Under an inert atmosphere, 200 mg (0.61 mmol) of compound 7 were solubilized in 15 ml of acetic acid. A commercial solution of 48% HBr in water (1 ml) (exothermic reaction) was added dropwise to the reaction mixture. The final solution was stirred at reflux for 3 days. After cooling, the reaction was diluted by the addition of water, then neutralized with a 10% sodium hydroxide solution (pH = 6-7). The product was extracted with dichloromethane (twice). The organic phase was dried over MgSO 4, then evaporated under reduced pressure. The residue obtained was purified by chromatography on a silica column (eluent CH 2 Cl / MeOH 9: 1) to give 61 mg (35) of compound 9. 2. Method B: Under an inert atmosphere, 1.0 g (3.1 mmol) of compound 7 were solubilized in 15 ml of dichloromethane.

At 0 ° C, 1.81 ml (19.0 mmol, 6 eq) of boron tribromide were added dropwise (exothermic reaction) to the reaction mixture. The final solution was stirred at room temperature for 18 hours. The reaction was hydrolyzed by addition (dropwise) of acne, then neutralized with a 10% sodium hydroxide solution (pH = 6-7). The product was extracted with dichloromethane (twice). The organic phase was dried over MgSO, then evaporated under reduced pressure. The obtained residue was purified on a silica column (eluent CH2Cl2 / MeOH 9: 1) to give 688 mg (76%) of compound 9.

.PF > 280 ° C (AcOEt) At NMR (250 MHz, DMSO-d5): d 3.53 (s, 3H, CH3), 6.25 (s, 2H, HAr), 6.76 (d, 2H, J = 8.8 Hz, HAr), 7.47 (d, 2H, J = 8.8 Hz, HAr), 7.92 (s, 1 H, HAr), 9.42 (s, 1H, OH), 10.00 (s, ÍH, OH), 10.35 (s, 1H, OH). 13C NMR (62.90 MHz, DMSO-d6): d 29.7, 91.8, 96.5, 103. 5, 114.7 (2), 124.3, 128.4. 129.7 (3), 141.7, 155.9, 156. 7, 160.6, 161.1. i ^ l a «^ ^ ^.

.SM (ion spray): m / z 284 (M + l) ' Analysis calculated for C? 6H? 3N04: C, 67.84; H, 4.63; N, 4.94. Found: C, 67.68; H, 4.46; N, 4.78.

EXAMPLE 8: 5, 7-Dimethoxy-3- (4-methoxyphenyl) -1-methyl-1,2-dihydroxy-2-quinolintio cetane (Compound 10) Under nitrogen atmosphere, 500 mg (1.5 mmol) of compound 7 was dissolved in 30 ml of toluene. To this reaction mixture was added 870 mg (2.1 mmol, 1.4 eq) of Lawesson's reagent. The reaction was refluxed for 12 hours. After cooling, the solvent was evaporated. The residue obtained was purified by chromatography on a silica column (AcOEt / EP 3: 7) to give 376 mg (72%) of compound 10.

.PF 176-177 ° C (AcOEt / EP) .IR (KBr) 1613, 1570, 1512 cm "1 A NMR (250 MHz, CDC13): d 3.84 (s, 3 H, OCH 3), 3.91 (s, 3 H, OCH 3), 3.95 (s, 3 H, OCH 3), 4.39 (s, 3H, NCH3), 6.39 (d, ÍH, J = 2.0 Hz, HAr), 6.56 (d, ÍH, J - 2.0 Hz, HAr), 6.93 (d, 2H, J = 7.5 Hz, HAr) , 7.43 (d, 2H, J = 7.5 Hz, HAr), 7.97 (s, ÍH, HAr). 13 C NMR (62.90 MHz, CDCl 3): d 39.5, 55.2, 55.6, 55.9, 91.1, 94.6, 109.9, 113.1 (2), 126.6, 130.8 (2), 134.3, 138.6, 142.7, 157.6, 158.8, 162.7, 184.5.

.SM: m / z 342 (M + l) + Calculated analysis for C19H19NO3S: C, 66.84; H, 5.61; N, 4.10. found: C, 66.70; H, 5.53; N, 4.03.

EXAMPLE 9: 2- [5, 7-dimethoxy-3- (4-hydroxy-phenyl) -2-oxo-l, 2-dihydro-l-quinolinyl] ethyl ace (Compound 11) .it, - • S?) &** z ~ iS Under nitrogen atmosphere, 1.0 g (3.2 mmoles) of compound 1 were solubilized, in 30 ml of anhydrous N, N-dimethylformamide (DMF). At 0 ° C, 115 mg (4.8 mmol, 1.5 eq) of NaOH, previously washed in petroleum ether, were added in small portions to the reaction solution (exothermic reaction). A solution of ethyl bromoacetate (0.72 ml, 6.4 mmol, 2 eq.) In 5 ml of DMF was added to the medium. The reaction was heated for 2-3 hours at 90 ° C. After cooling, water was poured over the reaction mixture, then it was stirred for 15 minutes. The solution was extracted with ethyl acetate (twice). The organic phase was dried over MgSO, then evaporated under reduced pressure. The residue obtained was purified by chromatography on a silica column (CH2Cl2 / AcOEt 7: 3) to give 890 mg (70%) of compound 11 and 318 mg (25%) of derivative lia.

Compound 11: .PF 160-161 ° C (AcOEt / EP) .IR (KBr) 1735, 1647, 1609 cm "1 A NMR (250 MHz, CDC13): d 1.6 (t, 3H, J = 7.1 Hz, COOCH2CH.), 3.83 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 3.92 (s, 3H, OCH3 ), 4.22 (q, 2H, J = 7.1 Hz, COOCH2CH3), 5.10 (S, 2H, CH2CO), 6.14 (d, ÍH, J = 2.0 HZ, HAr), 6.30 (d, ÍH, J - 2.0 Hz, HAr), 6.94 (d, 2H, J = 7.5 Hz, HAr), 7.69 (d, 2H, J = 7.5 Hz, HAr), 8.18 (s, ÍH, HAr). 13C NMR (62.90MHZ, CDC13): d 14.2, 44.8, 55.3, 55.5, 55.9, 61.6, 90.0, 92.8, 106.2, 113.5 (2), 126.6, 129.6, 130.1 (2), 131.0, 141.1, 157.8, 159.2, 161.9, 162.5. 168.4.

SM (ion spray): m / z 398 (M + l) • analysis calculated for C22H23N06: C, 66.49; H, 5.83; N, 3.52. Found: C, 66.60; H, 6.03; N, 3.75.

Composed lia: 2- ([5,7-Dimethoxy-3- (4-methoxyphenyl) -2-quinolinyl] oxy) ethyl acetate .PF 95-96 ° C (AcOEt / EP) .IR (KBr) n 1754, 1622, 1516, 1265 cm "1 At NMR (250 MHz, CDC13): d 1.27 (t, 3H, J - 7.1 Hz, CH3) 3.86 (s, 3H, OCH3), 3.91 (s, 3H, OCH3), 3.93 (s, 3H, OCH3), 4.24 (q, 2H, J - 7.1 Hz, OCH2), 5.05 (s, 2H , N CH2), 6.40 (d, ÍH, J = 2.0 Hz, HAr), 6.76 (d, ÍH, J = 2.0 Hz, HAr), 6.98 (d, 2H, J = 9.0 Hz, HAr), 7.68 (d) 2H, J = 9.0 Hz, HAr), 8.30 (s, ÍH, HAr). 13C NMR (62.90 MHz, CDC13): d 14.2, 55.3, 55.5, 55.7, 60.9, 62.7, 96.2, 98.6, 113.4, 113.7 (2), 121.7, 129.2, 130. 6 (2), 132.8, 147.3, 156.3, 158 159.1, 161.4, 169.5 , SM (ion spray): m / z 398 (M + l) Analysis calculated for C2 H23N? 6: C, 66.49; H, 5.83; N, 3.52. Found C, 66.63; H, 5.90; N, 3.60.

EXAMPLE 10: 3- [Methyl 5- (7-dxmethoxy-3- (4-hydroxy-phenyl) -2-oxo-l, 2-dihydro-l-quinolinyl] propanoate (Compound 12) Under a nitrogen atmosphere, 1.0 g (3.2 mmol) of compound 1 was solubilized in 20 ml of anhydrous N, N-dimethylformamide (DMF) in the presence of 2.9 ml of methyl acrylate (32.0 mmol, 10 eq). At 0 ° C, 2-3 drops of triton B were added to the reaction solution. The mixture was stirred for 4 h at room temperature. DMF and methyl acrylate were evaporated under reduced pressure. The residue obtained was taken up again in the ethyl acrylate and washed twice with water. The organic phase obtained was dried over MgSO4, then evaporated under reduced pressure. The crude product was purified by chromatography on a silica column (CH2Cl / AcOEt 8: 2) to give 1.06 g (83%) of compound 12.

.PF 100-101 ° C (AcOEt) .IR (KBr) 1725, 1638 cm "1 NMR (250 MHz, CDC13): d 2.78 (t, 2H, J = 8.0 Hz, CH2), 3.68 (s, 3H, COOCH3), 3.80 (s, 3H, OCH3), 3.88 (s, 6H, OCH3) , 4.57 (t, 2H, J = 8.0 Hz, CH2), 6.26 (d, 1 H, J = 2.0 Hz, HAr), 6.46 (d, ÍH, J = 2.0 Hz, HAr), 6.92 (d, 2H, J = 8.8 Hz, HAr). 7.66 (d, 2H, J = 8.8 Hz, HAr), 8.11 (s, ÍH, HAr). 13 C NMR (62.90 MHz, CDC13): d 31.9, 39.1, 51.8, 55.2, 55.5, 55.7, 89.8, 92.6, 106.2, 113.4 (2), 126.5, 129.5, 129.9 (2), 130.3, 140.5, 157.6, 159.0, 161.7, 162.4, 172.0.

.SM (ion spray): m / z 398 (M + l) + Analysis calculated for C2 H23NO6: C, 66.49; H, 5.83; N, 3.52. Found: C, 66.55; H, 5.70; N, 3.50.

EXAMPLE 11: 2- [5,7-dimethoxy-3- (4-methoxyphenyl) -2-oxo-1,2-dihydro-l-quinolinyl] benzyl acetate (Compound 13) Under nitrogen atmosphere, 300 mg (0.96 mmoles) of compound 1 was solubilized in 10 ml of anhydrous N, N-dimethylformamide (DMF). At 0 ° C, 35 mg (1.40 mmol, 1.5 eq) of NaH, previously washed in petroleum ether, were added in small portions to the reaction solution (exothermic reaction). A solution of benzyl bromoacetate (0.31 ml, 1.90 mmoles, 2 eq.) Diluted in 5 ml of DMF was added to the medium. The reaction was heated for 2 h at 90 ° C. After cooling, water was poured over the reaction mixture, then the latter was stirred for 15 min. The solution was extracted with dichloromethane (twice). The organic phase was dried over MgSO 4, then evaporated under reduced pressure. The residue obtained was purified by chromatography on a column of silica (eluent (CH2C1) to give 317 mg (72%) of compound 13 and 88 mg (20%) of derivative 13a.

Compound 13: PF 199-200 ° C (Et20 wash) IR (KBr) 1748, 1642, 1617 cm -i ? NMR (250 MHz, CDC13): d 3.68 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 3.92 (s, 3H, 5.16 (s, 2H, CH2), 5.21 (s, 2H, CH2), 6.03 (d, ÍH, J = 2.0 Hz, HAl), 6.27 (d, ÍH, J = 2.0 Hz, HAr), 6.94 (d, 2H, J = 7.5 Hz, HAr), 7.25-7.32 (m, 5H, HAr), 7.68 (d, 2H, J 7.5 Hz, HAr), 8.17 (s, ÍH, HAr ). 13C NMR (62.90MHZ, CDC13): d 44.7, 55.3, 55.4, 55.8, 67.1, 89.8, 93.0, 106.2, 113.5 (2), 126.5, 128.3 (2), 128.4, 128.5 (2), 129.5, 130.1 (2), 131.1, 135.3, 141.0, 157.8, 159.2, 161.8, 162.4, 168.3.

.SM (ion spray): m / z 460 (M + l) + Compound 13a: 2- ([5,7-dimethoxy-3- (4-methoxyphenyl) -2-quinolinyl] oxy) benzyl acetate .PF 114-115 ° C (ether) .IR (KBr) n 1761, 1621, 1517 cm "1 NMR (250 MHz, CDC13): d 3.87 (s, 3H, 0CH3), 3.91 (s, 3H, OCH3), 3.95 (s, 3H, 0CH3), 5.17 (S, 2H, 0CH2), 5.27 ( s, 2H, 0CH2), 6.44 (d, ÍH, J = 2.0 Hz, HAr), 6.76 (d, 2H, J = 2.0 Hz, HAr), 7.00 (d, 2H, J = 8.0 Hz, HAr), 7.26 -7.38 (m, 5H, HAr), 7.71 (d, 2H, J = 8.0 Hz, HAr), 8.36 (s, ÍH, HAr). 13C NMR (62.90 MHz, CDC13): d 55.2, 55.4, 55.5, 62.6, 66.4, 96.2, 98.5, 113.4, 113.6 (2), 121.6, 128.0 (2), 128.4 (3), 129.0, 130.5 (2), 132.7, 135.6, 147.2, 156.1, 158.6, 159.0, 161.3, 169.3.

.SM (ion spray): m / z 460 (M + l) + 10 EXAMPLE 12: 2- [5,7-Dimethoxy-3- (4-methoxyphenyl) -2-oxo-l, 2-dihydro-l acid -quinolinyl] acetic (Compound 14) In a balloon, 1 g (2.2 mmol) of benzyl ester 13 in dioxane (30 ml) was solubilized. It was added to the reaction solution, palladium on charcoal 10% (100 mg). The debenzylation reaction was carried out by means of a Parr apparatus under 40 pounds per square inch of hydrogen at room temperature for 4 hours. The reaction medium was filtered over celite and the filtrate was evaporated under reduced pressure. The obtained crystalline product was washed with ether to give 764 mg (95%) of compound 14. .P.F. 179-180A (washed with Et20) .JR (KBr) 1732, 1614, 1583 cm "1 NMR (250 MHz, DMSO-d6): d 3.77 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 3.91 (s, 3H, OCH3) 5.02 (s, 2H, CH2), 6.46 (s) , ÍH, HAr), 6.47 (s, ÍH, HAr), 6.93 (d, 2H, J = 9.0 Hz, HAr), 7.62 (d, 2H, J = 9.0 Hz, HAr), 8.03 (s, ÍH, HAr) ). 10 13 C NMR (62.90 MHz, DMSO-d 6): d: 44.9, 55.5, 56.1, 56.6, 91.3, 93.3, 105.3, 113.8 (2), 125.7, 129.4, 130.1 (2), 130.4, 141.3, 157.6, 159.1, 161.3, 162.8, 170.1.

.SM (ion spray): m / z 370 (M + l) + Analysis calculated for C2oH? 9N06: C, 65.03; H, 5.18; N, 3.79. Found: C, 65.00; H, 5.25; N, 3.85.

EXAMPLE 13: 3- [5,7-dimethoxy-3- (4-methyl-phenyl) -2-oxoyl, benzyl-2-dihydro-l-quinolinyl] propanoate (Compound 15) Under a nitrogen atmosphere, 150 mg (0.48 mmoles) of compound 1 was dissolved in 10 ml of anhydrous N, N-dimethylformamide (DMF) in the presence of 782 mg (4.8 mmoles, 10 eq) of benzyl acrylate. To 0 of triton B were added to the reaction solution. The solution was stirred for 18 hours at room temperature. The solvents were evaporated under reduced pressure. The residue obtained was taken up in ethyl acetate and washed twice with water. The organic phase obtained was dried over MgSO4, then evaporated under reduced pressure. The crude product was purified by chromatography on a silica column (AcOEt / EP) to give 200 mg (88%) of compound 15.

.PF 124-125 ° C (Et20 / EP) .IR (KBr) 1731, 1635, 1600 cm-1 NMR (250 MHz, CDC13): d 2.86 (t, 2H, J = 8.0 Hz, COCH2), 3.84 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 3.92 (s, 3H, * j »g ^ 2j $» ¡OCH3), 4.63 (t, 2H, J = 8.0 Hz, NCH2) 5.14 (s, 2H, CH2Ph), 6.29 (d, ÍH, J = 2.0 Hz, HAr), 6.49 ( d, ÍH, J = 2.0 Hz, HAr), 6.94 (d, 2H, J = 7.5 Hz, HAr), 7.30-7.35 (m, 5H, HAr), 7.68 (d, 2H, J = 7.5 Hz, HAr) , 8.13 (s, ÍH, HAr). 13 C NMR (62.90 MHz, CDC13): d 32.2, 39.1, 55.2, 55.4, 55.7, 66.5, 89.7, 92.6, 106.2, 113.4 (2), 126.5, 128.1 (2), 128.2, 128.4 (2), 129.5 , 129.9 (2), 130.4, 135.5, 140.5, 157.6, 159.0, 161.7, 162.4, 171.3.

SM (ion spray): m / z 474 (M + l) + EXAMPLE 14: 3- [5,7-Dimethoxy-3- (4-methoxyphenyl) -2-oxo-1,2-dihydro-l-quinolinyl] propanoic acid (Compound 16) In a balloon, 1.0 g (2.1 mmol) of benzyl ester 15 in dioxane (30 ml) were solubilized. The 10% palladium on charcoal (100 mg) was added to the reaction solution. The debenzylation reaction was carried out by means of a Parr apparatus under 40 pounds per square inch of hydrogen for 48 h. The reaction medium was filtered over celite and the filtrate was evaporated under reduced pressure to give, after washing with ether, 780 mg (97%) of compound 16.

.PF 194-195 ° C (washing with Et20) .IR (KBr) 1724, 1637, 1612 1604 cm -i NMR (250 MHz, (DMSO-d5): d 2.60 (t, 2H, J = 7.5 Hz, COCH2), 3.78 (s, 3H, OCH3), 3.90 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 4.48 (t, 2H, J = 7.5 Hz, NCH2), 6.48 (d, ÍH, J = 1.8 Hz, HAr), 6.62 (broad s, HI, HAr), 6.95 (d, 2H, J = 8.8 Hz, HG), 7.62 (d, 2H, J = 8.8 Hz, HAr), 8.00 (s, ÍH, HAl). 13 C NMR (62.90 MHz, DMSO-d 6): d: 32.0, 38.9, 55.1, 55.7, 56.1, 90.6, 9-3.0, 105.0, 11 3.3 (2), 125.6, 129.3, 129.5, 129.8 (2), 140.5, 157.2, 158.7, 160.6, 162.4, 172.5.

.SM: m / z 384 (M + l) + Analysis calculated for C2? H2iN06: C, 65.79; H, 5.52; N, 3.65. Found: C, 65.60; H, 5.51; N, 3.70.

EXAMPLE 15: N, N-Diethyl-3- [5,7-dimethoxy-3- (4-methoxyphenyl) -2-oxo-l, 2-dihydro-l-quinolinyl] propanamide (Compound 17) Under nitrogen atmosphere, 1.0 g (2.6 mmol) of compound 16 was solubilized in 25 ml of anhydrous N, N-dimethylformamide (DMF). At 0 ° C, 353 mg (2.6 mmoles) of hydroxybenzotriazole and 540 mg (2.6 mmoles) of cyclohexylcarbodiimide were added to the reaction solution. The reaction was stirred 10 minutes at 0 ° C, before adding 0.26 ml (2.6 mmol) of diethylamine. The final solution was stirred 2 h at 0 ° C, then 24 h at room temperature. The dicyclohexylurea was removed by filtration. The filtrate was extracted with ethyl acetate (twice). The collected organic phase was washed several times with water. The organic phase was dried over MgSO 4, then evaporated under reduced pressure. The residue obtained was purified by chromatography on a silica column (CH2Cl2 / AcOEt 7: 3) to give 680 mg (60%) of compound 17.

.PF 137-138 ° C (wash with AcOEt) .IR (KBr), 1636, 1617 cm "1 A NMR (250 MHZ, (CDC13): d 1.07-1.21 (M, 6H, CH3), 2.78 (t, 2H, J = 8.0 Hz, COCH2), 3.30 (q, 2H, J = 7.0 Hz, NCH2), 3.39 (q, 2H, J = 7.0 Hz, NCH2), 3.84 (s, 3H, OCH3), 3.91 (s, 3H, OCH3), 3.94 (s, 3H, OCH3), 4.65 (t, 2H, J = 8.0 Hz, NCH2), 6.29 (d, ÍH, J = 2.0 Hz, HAr), 6.73 (d, ÍH, J = 2.0 Hz, HAr), 6.94 (d, 2H, J = 7.5 Hz, HAr), 7.67 (d, 2H, J = 7.5 Hz, HAr), 8.15 (s, ÍH, HAr). 1 C NMR (62.90 MHz, CDCl 3): d; 13.1, 14.4, 31.0, 40.1, 40.5, 42.2, 55.3, 55.8 (2), 89.9, 93.1, 106.3, 113.5 (2), 126.6, 129.7, 130.0 (2), 130.5, 140.9, 157.6, 159.1, 162.1, 162.6 169.9 . SM (ion spray: m / z 439 (M + l) + Calculated analysis for C25H30N2O5: C, 68.47; H, 6.90; N, 6.39. Found: C, 68.27; H, 6.80; N, 6.40.

EXAMPLE 16: N, N-Diethyl-2- [5,7-dimethoxy -3- (4-methoxyphenyl) -2-oxo-l, 2-dihydro-l-quinolinyl] acetamide (Compound 18) Under a nitrogen atmosphere, 1.0 g (3.2 mmol) of compound 1 was solubilized in 30 ml of anhydrous N, N-dimethylformamide (DMF). At 0 ° C, 115 mg (4.8 mmol, 1.5 eq) of NaH, previously washed in petroleum ether, were added in small portions to the reaction solution (exothermic reaction). A solution of 2-chloro-N, N-diethylacetamide (0.88 ml, 6.4 mmol, 2 eq.) Diluted in 5 ml of DMF was added to the medium. The reaction was heated for 3 h at 90 ° C. After cooling, water was poured over the reaction mixture. The reaction solution was extracted with ethyl acetate (twice). The organic phase obtained was dried over MgSO4, then evaporated under reduced pressure. The obtained residue was purified by chromatography on silica column 20 (CH2Cl2 / AcOEt 7: 3) to give 820 mg (61%) of compound 18 and 408 mg (30%) of derivative 18a.

Compound 18: 25 PF 178- 179 ° C (AcOEt) «M.» - ^ a », t. . I. . • to. , _ _. . . ,, - .. - z .... __. , .-, *. t * An ?? rn »*» * .IR (KBr) 1642, 1617, 1601 cm "1 A NMR (250 MHz, CDC13): d 1.10-1.23 (m, 6H, CH3), 3.38-3.49 (m, 4H, CH2), 3.83 (s, 3H, OCH3), 3.86 (s, 3H, OCH3), 3.91 (s, 3H, OCH3), 5.17 (s, 2H, NCH2CO), 6.28 (d, IH, J = 2.0 Hz, Ar), 6.34 (d, IH, J = 2.0 Hz, Ar), 6.93 (d, 2H, J = 7.0 Hz, HAr), 7.56 (d, 2H, J = 7.0 Hz, HAr), 8.17 (s, ÍH, HAr). 13C NMR (62.90 MHz, CDC13): d 13.0.14.2, 40.9, 41.6, 45. 3, 55.3, 55.15, 55.8, 90-8, 92.8, 106.3, 113.4 (2), 126. 6, 129.9, 130.1 (2), 131.0, 141.7, 157.6, 159-0, 161.9, 162.3, 166.3.

.SM (ion spray): m / z 425 (M + l) + Analysis calculated for C24H28N20s: C, 67.91; H, 6.65; N, 6.60. Found: C, 67.62; H, 6.44; N, 6.50.

Compound 18a: N, N-diethyl-2 - ([5,7-dimethoxy-3- (4-methoxyphenyl) -2-quinolinyl] oxy) acetamide (18a) .

.PF 146-147 ° C (AcOEt / EP) .IR (KBr) n 1654, 1624, 1517 cm "1 At NMR (250 MHz, CDC13): d 1.14 (t, 3H, J - 7.5 Hz, CH3), 1.28 (t, 3H, J = 7.5 Hz, CH3), 3.36-3.47 (m, 4H, NCH2), 3.85 (s, 3H, OCH3), 3.91 (s, 3H, OCH3), 3.93 ( s, 3H, OCH3), 5.17 (s, 2H, NCH2), 6.38 (d, IH, J = 2.0 Hz, Ar), 6.73 (d, IH, J - 2.0 Hz, Ar), 6.97 (d, 2H, J - 9.0 Hz, HAr), 7.75 (d, 2H, J = 9.0 Hz, HAr), 8.28 (s, 1H, HAr). 13C NMR (62.90 MHz, CDC13): d 12.9, 14.2, 40.2, 55-2, 55.4, 55.6, 63.0, 95.8, 98.4, 113.3, 113.5 (2), 121.9, 129.2, 130.6 (2), 132.5, 147.3, 156.2, 158.9, 161.1, 167.3.

.SM (ion spray): m / z 425 (M + l) + Analysis calculated for C24H2s 2? 5: C, 67.91; H, 6.65; N, 6.60. Found: C, 67.85; H, 6.70; N, 6.51.

EXAMPLE 17: [5,7-Dimethoxy-3- (4-methoxyphenyl) -2-oxo-l, 2-dihydro-l-quinolinyl] acetonitrile (Compound 19) Under nitrogen atmosphere, 1.0 g (3.2 mmoles) of compound 1 was solubilized in 30 ml of anhydrous N, N-dimethylformamide (DMF). At 0 ° C, 115 mg (4.8 mmol, 1.5 eq) of NaH, previously washed in petroleum ether, was added little by little to the reaction solution. (exothermic reaction). A solution of bromoacetonitrile (0.45 ml, 6.4 mmol, 2 eq) diluted in 5 ml of DMF was added to the medium. The reaction was heated for 3 h to 90 ° C. After cooling, water was poured over the reaction mixture. The reaction solution was extracted with ethyl acetate (twice). The organic phase was dried over MgSO 4, then evaporated under reduced pressure. The residue obtained was purified by chromatography on a silica column (CH2Cl2 / Ac0Et 7: 3) to give 683 mg (61%) of compound 19 and 336 mg (30%) of derivative 19a.

Compound 19: .PF 208-209 ° C (AcOEt) .IR (KBr) 2216, 1660, 1607 cm "1 A NMR (250 MHZ, (CDC13): d 3.84 (s, 3H, OCH3), 3.94 (s, 3H, OCH3), 3.95 (s, 3H, OCH3), 5.29 (s, 2H, CH2), 6.36 (s) , 2H, HAr), 6.95 (d, 2H, J = 8.8 Hz, HAr), 7.65 (d, 2H, J = 8.8 Hz, HAr), 8.17 (s, ÍH, HAr). 13 C NMR (62.90 MHz, CDCl 3): d 30.4, 55.3, 55.8, 56.0, 90.0, 93.5, 106.2, 113.6 (2), 114.8, 126.3, 129.0, 130.0 (2), 131.7, 139.8, 158.1, 159.4.161.1, 163.0.

. SM (ion spray): m / z 351 (M + l) + Analysis calculated for C2oH? 8N204: C, 68.56; H, 5.18; N, 8.00 found: C, 68.30; H, 5.00; N, 7.90.

Compound 19a: 2- ([5,7-Dimethoxy-3- (4-methoxyphenyl) -2-quinolinyl] oxy) acetonitrile (Compound 19a) .PF 149-150 ° C (ether) .IR (KBr) n 1623, 1586, 1516, 1265 cm "1 A NMR (250 MHZ, (CDC13): d 3.87 (s, 3H, OCH3), 3.95 (s, 6H, OCH3), 5.17 (s, 2H, OCH2), 6.45 (d, ÍH, J = 2.0 Hz, HAr), 6.87 (d, ÍH, J = 2.0 Hz, HAr), 7.99 (d, 2H , J - 9.0 Hz, HAr), 7.54 (d, 2H, J = 9.0 Hz, HAl), 8.34 (s, ÍH, HAr). 13C NMR (62.90 MHz, CDC13): d 50.1, 55.3, 55.6, 55.7, 96.9, 98.6, 113.8 (2), 113.9, 116.1, 121.3, 128.4, 130.4, 130.5 (2), 133.5, 147.1, 156.3, 157.2, 129.3, 161.8.

.SM (ion spray): m / z 351 (M + l) + Calculated analysis for C20H? 8N2O: C, 68.56; H, 5.18; N, 8.00 Found: C, 68.42; H, 5.03; N, 7.88.

EXAMPLE 18: 3- [5,7-Dimethoxy-3- (4-methyl-phenyl) -2-oxo-1,2-dihydro-l-quinolinyl] -propanone tryl (Compound 20) Under nitrogen atmosphere, 500 mg (1.6 mmoles) of compound 1 and 0.8 ml (12 mmoles) of acrylonitrile were dissolved in 10 ml of anhydrous N, N-dimethylformamide (DMF). At 0 ° C, 2 drops of triton B were added to the reaction solution. The reaction was followed by plate in thin layer chromatography. At the end of the reaction, the solvents evaporated. The residue was taken up in ethyl acetate and washed several times with water. The organic phase was dried over MgSO4 then evaporated under reduced pressure. The residue obtained was purified by chromatography on a silica column (CH2Cl2 / AcOEt 7: 3) to give 365 mg (63%) of compound 20.

FP 156-157 ° C (AcOEt / EP) IR (KBr) 2241, 1639 c '-i NMR (250 MHz, CDCl3): d 2.88 (t, 2H, J = .7.1 Hz, CH2CN), 3.84 (s, 3H, 0CH3), 3.93 (s, 3H, OCH3), 3.94 (s, 3H, OCH3), 4.59 (t, 2H, J = 7.1 Hz, NCH2), 6.33 (d, ÍH, J = 1.8 Hz, HAr), 6.45 (d, 1 H, J = 1.8 Hz, HAr), 6.95 (d, 2H, J = 9.0 Hz, HAr), 7.66 (d, 2H, J = 9. 0 Hz, HAr), 8.17 (s, ÍH, HAr) • 13 C NMR (62.90 MHz, CDC13): d; 15.9, 39.4, 55.3, 55.7, 55.9, 89.9, 93.0, 106.4, 113.6 (2), 117.7, 126.6, 129.2, 130.0 (2), 131.1, 140.5, 158.0, 159.3, 161.8, 162.7.

.SM (ion spray): m / z 365 (M + l) + Analysis calculated for C2? H20NO4: C, 69.22; H, 5.53; N, 7.69. Found: C, 69.40; H, 5.40; N, 7.80.

EXAMPLE 19: 1- [2- (1 H-1,2,4-tetrazol-5-yl) ethyl] -5,7-dimethoxy-3- (4-methoxyphenyl) -1,2-dihydro-2- quinoline ketone (Compound 21) Under argon atmosphere, solubilized, 350 mg (0.90 mmoles) of compound 20 and 0.42 ml (1.53 mmoles) of tributyltin nitride in 20 ml of anhydrous toluene. The reaction solution was stirred at 105 ° C for 65 h. After cooling, the solvent was evaporated under reduced pressure. The residue obtained was purified by chromatography on a silica column (CH2Cl2 / MeOH 9: 1) to give 333 mg (85%) of compound 21.

.PF 234-235 ° C (wash with Et20) .IR (KBr) 1618, 1594 cm "1 NMR (250 MHz, DMSO-d6): d 3.33 (t, 2H, J = 6.0 Hz, CH2), 3.79 (s, 3H, OCH3), 3.89 (s, 3H, OCH3), 3.93 (s, 3H, OCH3), 4.67 (t, 2H, J = 6.0 Hz, CH2), 6.48 (s, ÍH, HAr), 6. 52 (s, ÍH, HAr), 6.96 (d, 2H, J = 9.0 Hz, HAr), 7.59 (d.2H, J = 9.0 Hz, HAr), 8.01 (S, ÍH, HAr) 13 C NMR (62.90 MHz, DMSO-d 6): d 21.4, 40.8, 55.1, 55.6, 56.1, 90.4, 93.0, 105.0, 113.3 (2), 125.5, 129.3, 129.6, 129.7 (2), 140.4, 153.7, 157.2, 158.7, 160.7, 162.4.

. SM (ion spray): m / z 408 (M + l) + Analysis calculated for C2? H20N5O: C, 61.91; H, 5.20; N, 17.19. found: C, 62.00; H, 5.19; N, 17.30.

EXAMPLE 20: l- [3-dimethylamino) propyl] -5,7-dimethoxy -3- (4-methoxy-enyl) -l, 2-dihydro-2-quinoline ketone (Compound 22) Under a nitrogen atmosphere, 1.0 g was solubilized (3.2 mmoles) of compound 1 in 20 ml of anhydrous N, N-dimethylformamide (DMF). At 0 ° C, 115 mg of NaH (4.8 mmol, 1.5 eq), previously washed in petroleum ether, were added little by little to the reaction mixture (exothermic reaction). A solution of 3-dimethylaminopropyl chloride (777 mg, 7.3 mmol, 2.25 eq) in 5 ml of DMF was added to the medium. The reaction was heated for 2-3 hours at 90 ° C. After cooling, water was poured over the reaction mixture, then the latter was stirred for 15 minutes. The solution was extracted with ethyl acetate (twice). The organic phase was dried over MgSO4, then evaporated under reduced pressure. The residue obtained was purified by chromatography on a silica column (Et20 / MeOH 8: 2, then CH ^ C MeOH 9: 1) to give 887 mg (70%) of compound 22 and 317 mg (25%) of derivative 22a.

Compound 22 MP 94-95 ° C (wash with Et20) .IR (KBr) 1635, 1617, 1598 cm - 'i A NMR (250 MHz, CDC13): d 1.91-2.04 (m, 2H, CH2), 2.28 (s, 6H, CH3), 2.46 (t, 2H, J = 7.2 Hz, CH2), 3.83 (s, 3H, OCH3), 3.91 (s, 3H, OCH3), 3.93 (s, 3H, OCH3), 4.36 (t, 2H, J = 7.2 Hz, CH2), 6.29 (d, ÍH, J = 2.0 Hz, HAr), 6.54 (d, ÍH, J = 2.0 Hz, HAr), 6.94 (d, 2H, J = 8.8 Hz, HAr), 7.68 (d, 2H, J = 8.8 Hz, HAr), 8.13 (S, ÍH, HAr) ). 13C NMR (62.90 MHz, CDC13): d 25.5, 41.8, 45.6 (2), 55.4, 55.5, 55.8, 57-1, 90.3, 92.6, 106.4, 113.5 (2), 126.9, 130.0, 130.1 (2), 130.3 , 141.1, 157.6, 159.1, 162.0, 162.3.

.SM: m / z 397 (M + l) t Calculated analysis for C23H28N20: C, 69.68; H, 7.12; N, 7.07. Found: C, 69.40; H, 6.97; N, 7.15.

Compound 22a: N, N-dimethyl-t-2- [5,7-dimethoxy-3- (4-metoxyphenyl) -2-quinolyl] oxy-l-propanamine (Compound 22a) .PF 54-55 ° C (ether) .IR (KBr) n 1621, 1584, 1515 cm -i NMR (250 MHz, CDC13): d 1.96-2.07 (m, 2H, CH2), 2.26 (S, 6H, NCH3), 2.47 (t, 2H, J = 6.5 Hz, NCH3), 3.84 (s, 3H, OCH3), 3.92 (s, 6H, OCH3), 4.53 (t, 2H, J = 6.5 Hz, 0CH3), 6.39 (d, ÍH, J = 2.2 Hz, HAr), 6.82 (d, ÍH, J = 2.2 Hz, HAr), 6.96 (d, 2H, J = 8.8 Hz, HAr), 7.57 (d, 2H, J = 8.8 Hz, HAr), 8.26 (s, ÍH, HAr). 13 C NMR (62.90 MHz, CDCl 3): d 27.0, 45.4 (2), 55.2, 55.5 (2), 56.6, 64.2, 95.8, 98.5, 112.7, 113.4 (2), 121.9, 129.6, 130.5 (2), 132.1, 147.9, 156.2, 158.8, 160.2, 161.2. . ? rieafcfcfe. " .SM (ion spray): m / z 397 (M + l) + Calculated analysis for C23H28N204: C, 69.68; H, 7.12; N, 7.07. Found: C, 69.53; H, 6.92; N, 7.16.

EXAMPLE 21: l- [2- (Dimethylamino) ethyl] -5,7-dimethoxy-3- (4-methoxyphenyl) -1,2-dihydro-2-quinoline ketone (Compound 23) Under nitrogen atmosphere, 250 mg (0.8 mmol) of compound 1 was solubilized in 15 ml of anhydrous N, N-dimethylformamide (DMF). At 0 ° C, 29 mg, (1.2 mmol, 1.5 eq) of NaH, previously washed in petroleum ether, were added little by little to the reaction solution. (exothermic reaction). A solution of 2-diemthylaminoethyl chloride (230 mg, 2.5 mmol, 3 eq) in 5 ml of DMF was added to the medium. The reaction was heated for 2-3 hours at 90 ° C. After cooling, water was poured over the reaction mixture, then the latter was stirred for 15 minutes. The solution was extracted with ethyl acetate (twice). The organic phase was dried over MgSO 4, then evaporated under reduced pressure. The residue obtained was purified by chromatography on a silica column (Et20 / AcOEt 3: 7, then CH2Cl2 / MeOH 9: 1) to give 205 mg (67%) of compound 23 and 92 mg (30% of derivative 23a).

Compound 23: .PF 113-114 ° C (wash with Et20) .IR (KBr) 1645,1617,1604 cm "1 At NMR (250 MHz, CDC13): d 2.39 (s, 6H, CH3), 2.65 (t, 2H, J = 7.8 Hz, CH2), 3.82 (s, 3H, OCH3), 3.90 (s, 3H, OCH3) , 3.91 (S, 3H, OCH3), 4.44 (t, 2H, J = 7.8 Hz, CH2), 6.28 (d, ÍH, J = 2.0 Hz, HAr), 6.49 (d, ÍH, J = 2.0 Hz, HAr), 6.94 (d, 2H, J = 8.8 Hz, HAr), 7.67 (d, 2H, J = 8.8 Hz, HAr), 8.12 (S, ÍH, HAr). 1 C NMR (62.90 MHz, CDCl 3): d 41.6, 45.8 (2), 55.3, 55.6, 55.8 (2), 90.1, 92.7, 106.4, 113.5 (2), 126.9, 129.8, 130. 1 (2), 130.4, 141.1, 157.7,159.1,161.9,162.4.

.SM (ion spray): m / z 383 (M + l) + Calculated analysis for C22H26N204: C, 69.09; H, 6.85; N, 7.32. Found: C, 69.37; H, 6.98; N, 7.51 Compound 23a: N, N-Dimethyl-2- [5,7-dimethoxy-3- (4-methoxy-enyl) -2-quinolyl] oxy-l-ethanamine MP 49-50 ° C (washing with ether) IR (KBr) n 1621, 1584, 1515 cpA A NMR (250 MHZ, CDC13): d 2.31 (s, 6H, NCH3), 2.77 (t, 2H, J = 6.0 Hz, NCH3), 3.85 (s, 3H, OCH3), 3.93 (s, 6H, OCH3), 4.62 (t, 2H, J = 6.0 Hz, OCH3), 6.39 (d, 1 H, J = 2.0 Hz, HAr), 6.81 (d, 1 H, J = 2.0 Hz, HAr), 6.94 (d, 2H, J = Hz, HAr), 7.58 (d, 2H, J = 8.8 Hz, HAr), 8.25 (s, ÍH, HAr). 13 C NMR (62.90 MHZ, CDCl 3): d 45.7 (2), 55.3, 55.5 (2), 57.8, 63.8, 95.9, 98.5, 112.9, 113.4 (2), 122.0, 129.5, 130.6 (2), 132.3, 147.8, 156.3, 158.9, 160.0, 161.3.

.SM (ion spray): m / z 383 (M + l) ' Calculated analysis for C22H 6N04: C, 69.09; H, 6.85; N, 7.32. Found: C, 69.30; H, 6.70; N, 7.29.

EXAMPLE 22: 8, 10-dimethoxy-6- (4-methoxy phenyl) -2,3-dihydro-lH, 5H-pyrido [3,2, l-ij] quinolin-1, 5-dic-tone (Compound 24) Under a nitrogen atmosphere, 63 mg of P205 and 500 mg of PPA were introduced into a balloon, then the mixture was added for 1 hour at 120 ° C. Compound 16 (100 mg, 0.26 mmol) was added, then the reaction was stirred for 45 min at 120 ° C. After cooling, a 2N soda solution was added until obtaining a pH 6-7. The crude product was extracted with CH2C12, (twice). The organic phase was dried over MgSO 4, then evaporated under reduced pressure. The obtained residue was purified by chromatography on a silica column (CH2Cl2 / MeOH 98: 2) to give 62 mg, 65%) of compound 24 PF 240-241 ° C (CH2C12 / EP) IR (KBr) 1678, 1649, 1634 cm " A NMR (250 MHz, CDC13): d 2.83 (t, 2H, J = 7.0 Hz, COCH2), 3.85 (s, 3H, OCH3), 4.04 (s, 6H, 0CH3), 4.54 (d, 2H, J = 7.0 Hz, NCH2), 6.32 (s, 1 H, HAr), 6.96 (d, 2H, J = 7.5 Hz, HAr), 7.68 (d, 2H, J = 7.5 Hz, HAr), 8.12 (s, ÍH, HAr). 13C NMR (62.90MHZ, CDCI3): d 37.6, 40.3, 55.3, 56.1, 56.5, 88.9, 103.5, 104.8, 113.6, (2), 127.6, 129.0, 129.8, 130.0 (2), 142.9, 159.4, 161.6, 161.7, 163.7,190.3.

.SM (ion spray): m / z 366 (M + l) "1 Analysis calculated for C2? H? 9N05: C, 69.03; H, 5.24; N, 3.83. Found: C, 68.80; H, 5.35; N, 4.00.

EXAMPLE 23: a) 5,7-Dimethoxy-3- (4-methoxyphenyl) -l-methyl-2- (methylsulfanyl) quinolium iodide (Compound 25) Under nitrogen atmosphere, 682 mg (2.0 mmol) of compound 10 was solubilized in 30 ml of anhydrous THF. At room temperature, 3.5 ml of methyl iodide (56 mmol, 28 eq) diluted in 5 ml of THF were added, then the reaction was stirred for 18 h under an inert atmosphere. The precipitate observed at the end of the reaction was filtered on glass fiber (washed with THF) to give 761 mg (79%) of compound 25.

.PF 156-157 ° C (washed with THF) A NMR (250 MHZ, CDC13): d 2.44 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 4.02 (s, 3H, OCH3), 4.28 (s, 3H, 0CH3), 5.03 (s, 3H, NCH3), 6.70 (d, ÍH, J = 1.5 Hz, HAr), 7.03 (d, 2H, J = 8. 5 Hz, HAr), 7.37 (s broad, ÍH, HAr), 7.45 (d, 2H, J = 8.5 Hz, HAr), 8.71 (s, ÍH, HAr). 13 C NMR (62.90 MHZ, CDCl 3): d 20.8, 46.5, 55.4, 56.7, 58.5, 92.9, 101.0, 114.4 (2), 117.6, 125.8, 128.9, 130.7 (2), 135.9, 138.8, 144.2, 157.4, 160.3, 167.7.

This compound is used quickly in the next stage. b) 5, 7-dimethoxy-3- (4-methoxyphenyl) -1-methyl-1,2-dihydro-2-quinoline ketone-2-phenylhydrazone (Compound 26) In a sealed tube, 200 mg (0.4 mmoles) of compound 25 and 0.28 ml (2.8 mmoles, 7 eq) of phenylhydrazine are solubilized in 5 ml of anhydrous ethanol. The reaction mixture is heated 18 h at 90 ° C. After cooling, the ethanol was evaporated under reduced pressure. The residue was taken up again in CH2C12, then washed twice with a solution of sodium bicarbonate. The organic phase was dried over MgSO 4, then evaporated under reduced pressure. The residue was taken back into methanol where < ^^^^^^^^^^^^^^ ^^^^ the final product precipitates. The latter was isolated by filtration (washing with MeOH) to give 102 mg (60%) of compound 26.

.PF 148-149 ° C (washed with MeOH) .IR (KBr) 3340, 1602, 1599 ccm-1 NMR (250 MHz, CDC13): d 3.58 (s, 3H, CH3), 3.85 (s, 3H, OCH3), 3.86 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 6.04 ( s, 1 H, HAl), 6.14 (s, 1 H, HAr), 6.48 (s broad, ÍH, NH). 6.56-6.67 (m, 3H, HAr), 6.94 (d, 2H, J = 8.8 Hz, HAr), 7.11 (t, 2H, J = 7.7 Hz, HAr), 7.28 (s, 1 H, HAr), 7.28 -7.34 (m, 13C NMR (62.90 MHz, CDC13): d 33.3, 55.4 (2), 55.6, 89.6 (2), 111.6, 113.8 (2), 117.8, 125.9, 128.3, 128.9 (3), 129.5 (2), 130.5, 146.2 , 157.2, 159.2 (2), 162..3.

Analysis calculated for C25H25 3? 3: C, 72.27; H, 6.06; N, 10.11. Found: C, 72.01; H, 5.86; N, 10.02.

EXAMPLE 24: 5, 7-dimethoxy-3- (4-methyl-phenyl) -1-methyl-1,2-dihydro-2-quinoline ketone -2- (2-pyridyl) hydrazone (Compound 27) In a sealed tube, 150 mg (0.31 mmol) of compound 25 and 237 mg (2.2 mmol, 7 eq) of 2-hydrazinopyridine in 5 ml of anhydrous ethanol were solubilized. The reaction mixture is heated 18 h at 90 ° C. After cooling, the ethanol was evaporated under reduced pressure. The residue was taken up again in CH2C12, then washed twice with a solution of sodium bicarbonate. The organic phase was dried over MgSO4 then evaporated under reduced pressure. The residue was taken back into methanol in which the final product precipitates. The latter was filtered (washed with MeOH) to give 75 mg (58%) of the orange compound 27.

.PF 182-183 ° C (washed with MeOH) .IR (KBr) 3353, 1628, 1593 cm "1 A NMR (250 MHZ, CDC13): d 3.61 (s, 3H, NCH3), 3.87 (s, 6H, OCH3), 3.90 (s, 3H, OCH3), 6.07 (s, ÍH, HAr), 6.17 (s, ÍH, HAr), 6.51-6.55 (m, 1 H, HP? R), 6.94-7.01. (m, 3H, HAr + Hp? r), 7.14 (broad s, ÍH, NH), 7.32-7.36 (m, 3H, HAr) 7.48 (t, ÍH, J = 7.3 Hz, Hpyr), 7.91 (d, ÍH, J = 4.3 Hz, HPyr). 13C NMR (62.90 MHz, CDC13): d 33.2, 55.3, 55.4, 55.6, 89.7 (2), 104.7, 105.7, 113.4, 114.1 (2), 122.9, 129.0, 129. 2 (2), 130.1, 137.5, 140.7, 143.7, 147.8, 157.3, 157.4, 159.2, 162.4.

.SM (ion spray): m / z 417 (M + l) + Analysis calculated for C24H? 4N403: C, 69.21; H, 5.81; N, 13.45. Found: C, 69.50; H, 6.04; N, 13.28.

EXAMPLE 25 a) N- (2-methoxyphenyl) -2- (4-methoxyphenyl) acetamide (Compound 30) Under a nitrogen atmosphere, 0.46 ml (4.2 mmol) of o-anisidine in toluene (7 ml) was diluted at 0 ° C. A dilution of 4-methoxyphenylacetyl chloride (0.63 ml, 4.1 mmol) in 5 ml of toluene was added dropwise to the medium. The reaction mixture was stirred at room temperature for 1 h, then the medium was hydrolyzed with a cold solution of sodium bicarbonate. The biphasic system was vigorously stirred for 30 minutes, then the organic phase was collected. The aqueous phase was extracted with ethyl acetate (twice). The organic phase was dried over MgSO 4, then evaporated under reduced pressure. The residue obtained was taken again in petroleum ether, this operation involves the precipitation of the investigated derivative. The crystals, thus formed, were collected by filtration to give 1.0 g (91%) of compound 30.

.PF 47-48 ° C (toluene) .IR (KBr) n 3375, 1667, 1597 cm "1 NMR (250 MHz, CDC13): d 3.68 (s, 2H, CH2), 3.72 (s, 3H, OCH3), 3.82 (s, 3H, OCH5), 6.79 (dd H, J = 1.5, 8.0 Hz, HAl), 6.89-7.03 (m, 4H, HAr), 7.25 (d, 2H, J == 8.8 Hz, HAr), 7. 79 (s broad, ÍH, NH), 8.33 (dd, ÍH, J = 1.5, 8.0 Hz, HAr). 13C NMR (62.90 MHz, CDC13): d 44.2, 55.3, 55.7, 109.9, 114.4 (2), 119.5, 121.0, 123.6, 126.6, 127.6, 130.7 (2), 147.8, 158.9, 169.3.

.SM (ion spray): m / z 272 (M + l) * b) 8-methoxy-3- (4-methoxyphenyl) -1,2-dihydro-2-quinoline ketone (Compound 31) Under nitrogen atmosphere and at -30 ° C, 0.31 ml (4.0 mmol, 1.5 eq) of N, N-dimethylformamide was added dropwise to 1.75 ml (19 mmol, 7.5 eq) of POCI3. The medium was stirred for 15 minutes at -30 ° C, then 723 mg of amide 30 (2.7 mmol) was added. With stirring, the reaction mixture was brought to room temperature, then the reaction was heated at 75 ° C for 1.5 hours. At the end of the reaction, this solution was poured on stacked ice, neutralized with 30% ammonia solution. %, then extracted with dichloromethane. The organic phase was dried over MgSO, then evaporated. The obtained residue was dissolved in 4.75 ml of glacial acetic acid and 0.15 ml of water, then the final solution was heated to reflux for 3 h. The acetic acid was evaporated. The residue was solubilized in water, neutralized with a 25% sodium hydroxide solution, then finally extracted with dichloromethane. The organic phase was dried over MgSO 4, then evaporated under reduced pressure. The residue was taken again in ethyl acetate, this operation involves the precipitation of the final product. The crystals thus obtained were filtered to give 75 mg (10%) of compound 10 31.

The overall yield of the synthesis applied to obtain the compound 31 is 9%.

.PF 148-149 ° C (AcOEt) .IR (KBr) n 1652, 1625, 1606, 1541 cm -i A NMR (250 MHz, DMSO-d6): d 3.79 (s, 3H, OCH3), 3.90 (s, 3H, OCH3), 6.99 (d, 2H, J = 8.8 Hz, HAr), 7.09-7.15 (m, 2H, HAr), 7.29 (dd, ÍH, J = 3.2, 6.0 Hz, HAr), 7.74 (d, 2H, J = 8-8 HZ, HAr), 8.03 (s, ÍH, HAr), 10.90 (s broad, ÍH, NH). ^^^^? ^^^^^ 13C NMR (62.90MHZ, DMSO-d6): d 55.2, 56.0, 110.5, 113.4 (2), 119.6, 120.0, 121.8, 127.9, 128.5, 129.9 (2), 131.6, 136.4, 145.3, 159.1, 160.7.

.SM (ion spray): m / z 282 (M + l) + Analysis calculated for C1-7H15NO3: C, 72.58; H, 5.37; N, 4.98. Found: C, 72.50; H, 5.50; N, 4.83.

EXAMPLE 26 a) N- (2, 5-dimethoxyphenyl) -2- (4-methoxyphenyl) acetamide (Compound 32) Ba or nitrogen atmosphere, 1.0 g (6.5 mmoles) of 2,5-dimethoxyaniline were solubilized in toluene (7 ml) at 0 ° C. A solution of 4-methoxyphenylacetyl chloride (1.0 ml), 6.5 mmol) diluted in 5 ml of toluene was added dropwise to the medium. The reaction mixture was stirred at room temperature for 1 hour, then the medium was hydrolyzed with a cold solution of sodium bicarbonate. The biphasic system was vigorously stirred for 30 minutes, then the organic phase was collected. The organic phase was extracted with ethyl acetate (twice). The organic phase was dried over MgSO 4, then evaporated under reduced pressure. The residue obtained was taken again in a minimum of petroleum ether, this operation involved the precipitation of the final product. The crystals formed were filtered on glass fiber to give 1.83 g (93%) of compound 32.

.PF 89-90 ° C (toluene) NMR (250 MHz, CDCl 3): d 3.67 (s, 3 H, OCH 3), 3.68 (s, 2 H, CH 2), 3.75 (s, 3 H, OCH 5), 3.81 (s, 3 H, OCH 3), 6.53 (dd, ÍH, J = 3.0, 9.0 Hz, HAr), 6.71 (d, ÍH, J = 9.0 Hz, HAr), 6.92 (d, 2H, J = 8.8 Hz, HAr), 7.25 (d.2H, J = 8.8 Hz , HA), 7.82 (s broad, ÍH, NH), 8.80 (d, ÍH, J = 3.0 Hz, HAr). 13 C NMR (62.90 MHz, CDCl 3): d 44.2, 55.3, 55.7, 56.3, 105.5, 108.6, 110.9, 114.4 (2), 126.4, 128.3, 130.6 (2), 142.0, 153.9, 158-9, 169.3.

. SM (ion spray): m / z 302 (M + 1) + b) 5, 8-dimethoxy-3- (4-methoxyphenyl) -1,2-dihydro-2-quinoline ketone (Compound 33) Under a nitrogen atmosphere and at -30 ° C, 0.31 ml (4.0 mmol, 1.5 eq) of N, N-dimethylformamide was added dropwise to 1.75 ml (20 mmol, 7.5 eq) of POCl3. The medium was stirred for 15 minutes at -30 ° C, then 813 mg of amide 32 (2.7 mmol) was added. With stirring, the reaction mixture was brought to room temperature, then the reaction was heated at 75 ° C for 1.5 hours. After this lapse of time, the solution was poured on stacked ice, neutralized with a 30% ammonia solution, then extracted with dichloromethane. The organic phase was dried over MgSO 4, then evaporated. The residue obtained was taken again in 4.75 ml of glacial acetic acid and 0.15 ml of water, then the final solution was heated to reflux for 3 hours. The acetic acid was evaporated. The residue was solubilized in water, neutralized with a 25% sodium hydroxide solution, then finally extracted with dichloromethane. The organic phase was dried over MgSO, then evaporated under reduced pressure. The residue was taken back into ethyl acetate, this operation involved the precipitation of the final compound. The crystals thus obtained were filtered to give 378 mg (45%) of compound 33.

The overall yield of chemical synthesis to obtain compound 33 is 42%.

.PF 186-187 ° C (AcOEt) .IR (KBr) n 1639, 1571, 1515 cm '-i At NMR (250 MHz, CDC13): d 3.85 (s, 3H, OCH3), 3.90 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 6.49 (d, ÍH, J - 8.7 Hz, HAr), 6.84 (d, ÍH, J = 8.7 Hz, HAr), 6.97 (d, 2H, J = 8.8 Hz, HAr), 7.74 (d, J = 8.8 Hz, HAr), 8.19 (s, ÍH, HAr), 9.25 (s broad, ÍH, NH). 13C NMR (62.90 MHz, CDC13): d 55.2, 55.8, 56.2, 101.1, 109.7, 111.4, 113.6 (2), 128.7, 128.8, 130.0 (2), 131.4, 131.7, 139.4, 149.8, 159.5, 161.3.

.SM (ion spray): m / z 312 (M + l) +. Analysis calculated for ClsH? 7N04: C, 69.44; H, 5.50; N, 4.50. Found: C, 69.71; H, 5.59; N, 4.70.

EXAMPLE 27: 5, 7-dimethoxy-3-phenyl-1,2-dihydro-2-quinoline ketone (Compound 34) a) N- (3,5-dimethoxyphenyl) -2-phenylacetamide (compound 35) 10 Under a nitrogen atmosphere, 1.0 g (6.5 mmol) of 3,5-dimethoxy aniline in toluene (14 ml) was solubilized at 0 ° C. A solution of phenylacetyl chloride (0.86 ml, 6.5 mmol) in 10 ml of toluene was added dropwise to the medium. The reaction mixture was stirred at room temperature for 1 h, then the medium was hydrolyzed with a cold solution of sodium bicarbonate. The biphasic system was vigorously stirred for 30 minutes, then the organic phase was collected. The aqueous phase was extracted with ethyl acetate (twice). The organic phase was dried * dM * to - * - "(- • • • - - • '--- t. A m ^ i *. on MgSO4, then evaporated. The residue obtained was crystallized from toluene to yield 1.55 g (87%) of compound 35.

.PF 109-111 ° C (toluene) IR (KBr) n 3286, 1657, 1616 cm -i NMR (250 MHz, CDC13): d 3.70 (s, 2H, CH2), 3.74 (s, 6H, OCH3), 6.21 (t, ÍH, J = 2.2 Hz, HAr), 6.66 (d, 2H, J = 2.2 HZ, HAr), 7.09 (s broad, ÍH, NH), 7.30-7.40 (m, 5H, HAr). ljC NMR (62.90 MHZ, CDC13): d 44.9, 55.4 (2), 96.8, 97.9 (2), 127.7, 129.2 (2), 129.5 (2), 134.3, 139.4, 161.0 (2), 169.1.

.SM (ion spray): 272 (M + l) + b) 2-chloro-5,7-dimethoxy-3-phenyl-1,2-dihydroquinoline (Compound 36) Under nitrogen atmosphere and at -30 ° C, 0.64 ml (8.3 mmoles) were added dropwise., 1.5 eq) of N, N-dimethylformamide at 3.8 ml (41.0 mmol, 7.5 eq) of POCI3. the medium was stirred for 15 min at -30 ° C, then 1.5 g of amide 35 (5.5 mmol) was added. With stirring, the reaction mixture is brought to room temperature, then the reaction is heated at 75 ° C for 2.5 h. At the end of the reaction, this solution was poured onto the stacked ice, neutralized with a 30% ammonia solution, then extracted with dichloromethane. The organic phase was dried over MgSO 4, then evaporated. The obtained residue was purified by chromatography on a silica column (eluent: AcOEt / EP 3: 7) to give 800 mg (49%) of compound 36.

PF 148-150 ° C NMR (250 MHz, CDCl 3): d 3.93 (5, 6H, (0CH3), 6.51 (d, ÍH, J = 2.2 Hz, HAr), 6.97 (d, 1H, J = 2.2 Hz, HAr), 7.4- 7.54 (m, 5H, HAr), 8.36 (s, ÍH, HAr). 13 C NMR (62.9 MHZ, CDCl 3): d 55.6, 55.8, 98.6, 98.8, 115.6, 127.9, 128.1 (2), 129.7 (2), 131.2, 133.9, 138.1, 149. 2, 150.2, 156.1, 162.3 .SM (ion spray): m / z 301 (M + l) +, 303 (M + l) + c) 5,7-dimethoxy-3-phenyl-1,2-dihydro-2-quinoline ketone (Compound 34) Under a nitrogen atmosphere, they were mixed in a balloon 1. 52 g (9.9 mol) of 3, 5-dimethoxyanilyl and 2.30 g (12 mmol, 1.2 eq) of ethyl a-formyl-phenylacetate. The media was stirred for 1 h at room temperature. A solution of trimethylsilyl polyphosphate was added (PPSE), freshly prepared from 4.56 g (0.03 mole) of P2O5, 10.9 ml (0.17 mole) of hexamethyldisiloxane and 50 ml of 1,2-dichloroethane. The final mixture was brought to 100 ° C for 2 h. The heat was stopped, then ice was added to the reaction mixture. The latter is below neutralized by the addition of a saturated solution of sodium bicarbonate (addition little by little, exothermic reaction). The product was extracted with dichloromethane (a large amount is used). The organic phase was dried over MgSO 4, then evaporated under reduced pressure. The residue was taken again in ethyl acetate, this operation involved the precipitation of the desired compound. The final product was isolated by filtration on glass fiber. After partial concentration of the filtrate, the final product precipitated again. The solid was isolated again by filtration, this operation was repeated several times. Compound 34 (444 mg) was obtained in a yield of 16%.

.PF 257-258 ° C (AcOEt) .IR (KBr) n 1668, 1631, 1569, 1514 cm "1 NMR (250 MHz, DMSO-d6): d 3.81 (s, 3H, OCH3), 3.89 (s, 3H, OCH3), 6.36 (d, ÍH, J = 1.8 Hz, HAr), 6.45 (d, ÍH, J = 1.8 Hz, HAr), 7.28-7.42 (, 3H, 7.69 (d, 2H, J = 7.0 Hz, HAr, 8.00 (s, ÍH, HAr) 11.81 (s broad,? H). 13C RM? (62.90 MHz, DMSO-d6): d 55.5, 56.0, 90.0, 93.1, 104.5, 126.9, 127.3, 127.9 (2), 128.4 (2), 131.4, 136.7, 140.8, 156.8, 161.4, 162.2.

SM (ion spray): m / z 282 (M + l .Analysis calculated for C? 7H? 5? 03: C, 72.58; H, 5.37; ?, 4.98. Found: C, 72.29; H, 5.20; ?, 5.10.

EXAMPLE 28 a) N- (2-methoxyphenyl) -2-phenylacetamide (Compound 37) Under a nitrogen atmosphere, 1.37 ml (0.01 mmol) of o-anisidine was dissolved in toluene (14 ral) at 0 ° C. a solution of phenylacetyl chloride (1.62 ml, 0.01 mol) in 5 ml of toluene was added dropwise to the medium. The reaction mixture was stirred at room temperature for 1 h, then the medium was hydrolyzed with a cold solution of sodium bicarbonate. The biphasic system was stirred vigorously for 30 minutes, then the organic phase was collected. The aqueous phase was extracted with ethyl acetate (twice). The organic phase was dried over MgSO 4, then evaporated under reduced pressure. The obtained residue was dissolved in a minimum of toluene, this operation involved the precipitation of the final product. After filtration on glass fiber, 2.7 g (92%) of compound 37 were isolated.

^ | MUL | H UM .PF 80-81 ° C (toluene) [PF 85 ° C; C. Yamagami et al. Chem. Pharm. Bull. 1984, 32, 5003-5009] .IR (KBr) n 3287, 1652, 1598 c "1 NMR (250 MHz, CDC13): d 3.72 (s, 3H, CH3), 3.76 (s, 2H, CH3), 6.81 (dd, ÍH, J = 8.0, 1.8 Hz, HAr), 6.91-7.05 (, 2H , HAr), 7.21-7.37 (m, 4H, HAr), 7.80 (broad s, ÍH, NH), 8.35 (dd, ÍH, J = 8.0, 1.8 Hz, HAr). 10 13 C NMR (62.90 MHz, CDC 13): d 45.2, 55.7, 109.9, 119.5, 121.1, 123.7, 127.4, 127.6, 129.0 (2), 129.6 (2), 134.6, 147.8, 168.8.

.SM (ion spray): m / z 242 (M + l) + b) 8-methoxy-3-phenyl-1,2-dihydro-2-quinoline ketone (Compound 38) Under a nitrogen atmosphere and at -30 ° C, 1.3 ml (1.68 mol, 1.5 eq) of N, N-dimethylformamide were added dropwise to 7.3 ml (78 mmol, 7 eq) of P0C13. He • * - ** M »M» Wiißi? ^^ medium was stirred for 15 minutes at -30 ° C, then 2.7 g of amide 37 (0.01 mmol) were added. With stirring, the reaction mixture was brought to room temperature, then the reaction was heated at 75 ° C for 1.5 h. At the end of the reaction, this solution was poured onto stacked ice, neutralized with a 30% ammonia solution, then extracted with dichloromethane. The organic phase was dried over MgSO 4, then evaporated. The residue was purified by chromatography on a silica column (AcOEt / EP 3: 7 = to give 650 mg (21%) of chlorinated derivative, after dissolution of the latter in 3.8 ml of glacial acetic acid and 0.12 ml of water, The final solution was heated to reflux for 3 hours.The acetic acid was evaporated, the residue was solubilized in water, neutralized with a 25% sodium hydroxide solution, then finally extracted with dichloromethane.The organic phase was dried over MgSO. , then evaporated under reduced pressure The residue was taken again in ethyl acetate, this operation involved the crystallization of the final product The crystals thus obtained were filtered to give 237 mg (40%) of compound 38.

The overall yield of the synthesis applied to obtain the compound 38 is 8%.

PF 188-189 ° C (AcOEt) .IR (KBr) n 1646, 1607, 1569 cm -i NMR (250 MHz, (DMSO-d6): d 3.92 (s, 3H, OCH3), 7.13-7.16 (, 2H, HAr), 7.30-7.46 (m, 4H, HAr), 7.74-7.77 (m , 2H, HAr), 8.09 (s, ÍH, HAr), 10.98 (s broad, ÍH, NH). 13 C NMR (62.90 MHz, DMSO-d 6): d: 56.5, 111.3, 120.3, 120.4, 122.4, 128.3 (2), 128.4, 128.7, 129.2 (2), 132.6, 136. 7, 138.2, 145.9, 16 1. 1.

.SM (ion spray): 252 m / z (M + l) + Calculated analysis for C 16 H 13 NO 2: C, 76.48; H, 5.21; N, 5.57. Found: C, 76.23; H, 5.14; N, 5.70.

EXAMPLE 29: 5,7-Acetoxy-3- (4-acetoxyphenyl) -1,2-dihydro-2-quinoline ketone (Compound 39) . ^ ^ ^ ^ ^ ^ l-^ ^ ^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ 9 (CRL8321) acetic anhydride and pipdin (8 ml, v / v) at 0 ° C. The reaction mixture was stirred at room temperature for 18 h. The medium was hydrolyzed by addition of water (10 ml) then extracted with dichloromethane (twice). The organic phase was dried over MgSO 4, then evaporated. The residue obtained was purified by chromatography on a silica column (AcOEt / CH2Cl2 1: 9) to give 220 mg (76%) of compound 39.

.PF 206-207 ° C (AcOEt) IR (KBr): n 1769, 1748, 1638, 1598, 1576, 1508 cm -i A NMR (250 MHz, (CDC1: d 2.31 (s, 3H, CH3), 2.33 (s, 3H, CHa), 2.40 (s, 3H, CH3), 3.72 (s, 3H, NCH3), 6.92 (d, ÍH, J = 2. 0 Hz, HAr), 7.03 (d, ÍH, J = 2.0 Hz, HAr), 7.14 (d, 2H, J = 8.5 Hz, HAr), 7.67 (d, 2H, J = 8.5 Hz , HAr), 7.78 (s, ÍH, HAr). 13C NMR (62.90 MHz, CDC13): d 20.8, 21.0, 21.2, 30.5, 105.2, 110.2, 111.8, 121.4 (2), 129.7, 130.3 (2), 131.5, 134.2, 141.0, 148.8, 150.7, 151.9, 161.2, 168.6, 168.8, 169.6. ^. . ^,,. . .. -. .. ".," _. ",, Jr ^. . .. . . .. z-. : > ÍA ^ AZA ^ A .SM (ionic pulverization): m / z 410 (M + l) " Analysis calculated for C22H1QN07: C, 64.54; H, 4.68; N, 3.42. Found: C, 64.83; H, 4.85; N, 3.57.

EXAMPLE 30: 3- [5,7-dimethoxy-3- (4-methoxy phenyl) -2-oxoyl, 2-dihydro-1-quinolinyl] butanni tryl (Compoteto 40) (CRLßJM) Under a nitrogen atmosphere, 400 mg (1.28 mol) of compound 1 (CRL8246) were solubilized in 10 ml of anhydrous N, N-dimethylformamide (DMF). At 0 ° C, 47 mg (1.92 mmoles, 1.5 eq) of sodium hydride, previously washed with petroleum ether, were added to the reaction solution (exothermic reaction), little by little. 4-Chlorobutyronitrile (0.23 ml, 2.57 ml, 2 eq) and sodium iodide (20 mg) were added to the medium. the reaction was heated for 3 h at 90 ° C. After cooling and evaporation of the DMF, water was poured on the residue. The aqueous solution was extracted with ethyl acetate (twice). The organic phase was dried over MgSO 4, then evaporated under reduced pressure. The obtained residue was purified by chromatography on silica column (CH2Cl2 / AcOEt 9: 1) to give 151 mg (31%) of compound 40a and 161 mg (33%) of derivative 40.

Compound 40: 5 .PF 157-158 ° C (AcOEt) .IR (KBr) n 11639, 1609, 1597, 1575, 1517 cm "1 A NMR (250 MHz, CDClj): d; 2.10-2.21 (m, 2H, CH), 2. 52 (t, 2H, J = 7.2 Hz, CH2CN), 3.83 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 3.93 (s, 3H, OCH3), 4.43 (t, 2H, J = 7.2 Hz, NCH2), 6.31 (d, ÍH, J = 2.2 HZ, HAr), 6.42 (cl, 1H, J = 2.2 Hz, HAr), 6.94 (d, 2H, J = 8.8 Hz, HAl), 7.66 (d, 2H, J = 8. 8 Hz, HAr), 8.15 (s, ÍH, HAr). 1? C NMR (62.90 MHz, CDC1: d 15.3, 23.6, 41.8, 55.4, 55.9, 56.0, 89.6, 93.1, 106.4, 113.6 (2), 119.5, 126.7, 129. 6, 130.1 (2), 130.8, 140.7, 157.9, 159.3, 161.2, 162.8.

.SM (ion spray): m / z 379 (M ++ l) + Calculated analysis for C22H22N204: C, 69.83; H, 5.86; N, 7.40. Found: C, 69.61; H, 55.97; N, 7.32. 25 ! ÉÍÉÍÍ-? - k - í - ÍMi ?? 1 - i - ^ - ^^ M ^^^ 2 - ([5,7-dimethoxy-3- (4-methoxyphenyl) -2-quinolinyl] oxy) butanonitrile (Compound 40a) Compound 40a: 10 PF 89-90 ° C (AcOEt) .IR (KBr) n 1624, 1607, 1582, 1515 cm "1 A NMR (250 MHz, CDC13): d 2.12-2.22 (m, 2H, CH2), 2.50 (t, 2H, J = 7.5 Hz, CH2), 3.87 (s, 3H, OCH3), 3.94 (s, 6H , OCH3), 4.61 (t, 2H, J = 7.5 HZ, CH2), 6.40 (d, ÍH, J = 2.2 Hz, HAl), 6.81 (d, ÍH, J = 2.2 Hz, HAr), 6.97 (d, 2H, J = 8.8 Hz, HA, 7.53 (d, 2H, J = 8.8 Hz, HAr), 8.27 (s, ÍH, 20 HAr). 13C NMR (62.9 MHz, CDCI3): d 14.6, 25.4, 55.4, 55.7, 55.8, 63.6, 96.2, 98.6, 113.6, 113.7, 113.7, 119.5, 122.5, 122.5, 129.5, 130.5, 2, 132.8, 147.9, 156.4, 159.1, 159.7, 161.6. 25 p-riaiÍn1? t «ÍH l ^ TÍ? ytA - t 1. 1 hour" . , t ". ^, ... .........," ...-_. ... ", Z .... Z..A.A. ^ it ^^^.

.SM (ion spray): m / z 379 (M * + l) .Analysis calculated for C2 :: H22N :: 04: C, 69.83; H, 5.86; N, 7.40. Found: C, 69.99; H, 5.72; N, 7.60.

EXAMPLE 31: a) N- (3,5-dimethoxyphenyl) -2- (4-benzyloxyphenyl) acetamide (Compound 41) Under nitrogen atmosphere, 238 mg were solubilized (1.6 mmoles) of 3,5-dimethoxyaniline in toluene (7 ml) at 0 ° C. A solution of 4-benzylphenylacetyl chloride (0.5 ml, 1.7 mmol) in 5 ml of toluene was added dropwise to the medium. The reaction mixture was stirred at room temperature for 2 h, then the medium was hydrolyzed with a cold solution of sodium bicarbonate. The biphasic system was vigorously stirred for 30 minutes, then the organic phase was collected. The aqueous phase was extracted with ethyl acetate (twice). The organic phase was dried over MgSO, then evaporated. The residue obtained was purified by chromatography on a silica column (AcOEt / EP) to give 300 mg (81% of compound 41.

.PF 122-123 ° C (AcOEt / EP) IR (KBr¡ n 291, 1659, 1610, 1595, 1513 cm " NMR (250 MHz, CDC13): d 3.66 (s, 2H, CH2), 3.74 (s, 3H, OCH3), 3.75 (s, 3H, OCH3), 5.08 (s, 2H, CH2), 6.21 (t, 0 H, J = 2.2 HZ, HAi), 6.65-6.66 (m, 2H, J = 2.2 HZ, HAr), 7.00 (d, 2H, J = 8.8 Hz, HAr), 7.08 (s, ÍH, NH), 7.24 (d, 2H, J = 8.8 Hz, HAr), 7.33-7.46 (m, 5H, HAr).

XC NMR (62.90 MHz, CDC13): d 44.2, 55.5 (2), 70.2, 5 96.9, 98.0 (2), 115.7 (2), 126.6, 127.6 (2), 128.2, 128.8 (2), 130.8 (2) , 136.9, 139.6, 158.4, 161.1 (2), 169.7.

.SM (ion spray): 378 (Mt + 1) Analysis calculated for C 3 H23N04: C, 73.19; H, 6.14; N, 3.71. found: C, 72.87; H, 5.97; N, 3.85. b) 5, 7-dimethoxy-3- (4-benzyloxyphenyl) -1,2-dihydro-2-quinoline ketone (compound 42) - - - rt l 1 ', * •' l _ > --- - - '- Í 1 l. «Yy-yy ^ t ^ S Under a nitrogen atmosphere and at -30 ° C, 0.31 ml (4.0 mmol, 1.5 eq) of N, N-dimethylformamide was added dropwise to 1.75 ml (19 mmol, 7.5 eq) of POCI3. The medium was stirred for 15 minutes at -30 ° C, then added 1.02 g of amide 41 (2.7 mmoles). With stirring, the reaction mixture was brought to room temperature, then the reaction was heated at 75 ° C for 1.5 hours. At the end of the reaction, this solution was poured on stacked ice, neutralized with 30% ammonia solution. %, then extracted with dichloromethane. The organic phase was dried over MgSO 4, then evaporated. The obtained residue was dissolved in 4.75 ml of glacial acetic acid and 0.15 ml of water, then the final solution was heated to reflux for 3 hours. The acetic acid was evaporated. The residue is Solubilized in water, neutralized with a 25% sodium hydroxide solution, then finally extracted with dichloromethane. The organic phase was dried over MgSO, then evaporated under reduced pressure. The residue was taken again in ethyl acetate, this operation involved the precipitation of the final product. The crystals well ^^ n ^ gll ^^ e-Mb e- ^ a-ü-i obtained were filtered to give 200 mg (20%) of compound 42. .PF 234-235 ° C (AcOEt) IR (KBr): n 1629, 1608, 1569, 1515 cm -i A NMR (250 MHZ, DMSO-d6): d 3.81 (s, 3H, OCH3), 3.90 (s, 3H, OCH3), 5.15 (s, 2H, CH2), 6.37 (s, 1H, HAr), 6.45 (s, ÍH, HAr), 7.04 (d, 2H, J = 8.8 Hz, HAr), 7.31-7.49 (m, 5H, HAr), 7.69 (d, 2H, J = 7.5 Hz, HAr) 7.97 (s, HIH), 11.76 (broad s, ÍH, NH). 13 C NMR (62.90 MHz, DMSO-d 6): d 55.4, 55.9, 69.2, 90.0, 15 93.0, 104.6, 114.3 (2), 126.4, 127.6 (2), 127.8, 128.4 (2) 129. 2, 129.6 (2), 130.2, 137.1, 140.5, L56.6, 157-7, 161.5,161.9.

.SM (ion spray): m / z 388 (M ++ 1) 20. Analysis calculated for C 24 H 2? N0: C, 74.40; H, 5.46; N, 3.62. Found: C, 74.26; H, 5.67; N, 3.52.

EXAMPLE 32: 25 a) N- (4-methoxyphenyl) -2-phenylacetamide (Compound 43) Under nitrogen atmosphere, 1.5 g (12.0 mmoles) of p-anisidine in toluene (7 ml) was solubilized at 0 ° C. A solution of phenylacetyl chloride 1.61 ml, 12.2 mmol) in 20 ml of toluene was added dropwise to the medium. The reaction mixture was stirred at room temperature for 2 hours, then the medium was hydrolyzed with a cold solution of sodium bicarbonate. The biphasic system was stirred vigorously for 30 minutes, then the organic phase was collected. The aqueous phase was extracted with ethyl acetate (twice). The organic phase was dried over MgSO 4, then evaporated. The residue obtained was purified by chromatography on a silica column (AcOEt / EP) 3: 7) to give 2.7 g (89%) of compound 43. 20 PF 118-119 ° C (AcOEt / EP) IR (KBr): n 3290, 1650, 1603, 1545, 1513 cm '-i XH NMR (250 MHz, CDC13): d 3.72 (s, 2H, CH2), 3.77 (s, 3H, OCH3), 6.81 (d, 2H, J = 9.0 Hz, HAr), 7.00 (s broad, ÍH, NH ), 7.28-7.43 (m, 7H, HAr). 13C NMR (62.90 MHz, CDC13): d d. 44.8, 55.6, 114.2 (2), 121.9 (2), 127.7, 129.3 (2), 129.7 (2), 130.8, 134.7, 156.7, 169.1.

.SM (ion spray): 242 (M ++ l) 10. Analysis calculated for C? 5H15N02: C, 74.67; H, 6.27; N, 5.80. Found: C, 74.79; H, 6.14; N, 5.95. b) 6-methoxy-3-phenyl-1,2-dihydro-2-quinoline ketone (Compound 44) Under nitrogen atmosphere and at -30 ° C, 0.96 ml (12.4 mmol, 1.5 eq) of N, N-dimethylformamide is added dropwise to 5.4 ml (58 mmol, 7.5 eq) of P0C13. The medium was stirred for 15 minutes at -30 ° C, then added 2.0 g of amide 43 (8.3 immoles). Under agitation, the mixture The reaction was brought to room temperature, then the reaction was heated at 75 ° C for 1.5 h. At the end of the reaction, this solution was poured onto stacked ice, neutralized with a 30% ammonia solution, then extracted with dichloromethane. The organic phase was dried over MgSO 4, then evaporated. The obtained residue was dissolved in 12.2 ml of glacial acetic acid and 0.4 ml of water, then the final solution was heated to reflux for 3 h. The acetic acid was evaporated. The residue was solubilized in water, neutralized with a 25% sodium hydroxide solution, then finally extracted with dichloromethane. The organic phase was dried over MgSO, then evaporated under reduced pressure. The residue was taken again in ethyl acetate, this operation involved the precipitation of the final product. The crystals thus obtained were filtered to give 585 mg (28%) of compound 44.

.PF 243-244 ° C (AcOEt) .IR (KBr) n 1645, 1618, 1569, 1503 cm "1 At NMR (250 MHz, DMSO-d6): d 3.80 (s, 3H, OCH3), 7.16 (dd, ÍH, J = 2.5, 8.9 Hz, HAr), 7.28 (d, ÍH, J = 8.9 Hz, HAr), 7.29 (d, ÍH, J = 2.5 Hz, HAr), 7.34-7.47 (m, 3H, HAr), --tÍkt --- U «« M-? --- - * - - - • * 7.76 (d, 2H, J = 6.8 HZ, HAr), 8.06 (s, 1 H, HAr), 11.85 (s broad, ÍH, NH). 13 C NMR (62.90 MHZ, DMSO-d 5): d 55.4, 109.4, 116.0, 119.5, 120.1, 127.8, 127.9 (2), 128.7 (2), 131.9, 132.9, 136. 4, 137.2, 154.2, 160.6.

.SM (ion spray): m / z 252 (Mt + 1) Analysis calculated for C? 6H13N02: C, 76.48; H, 5.21; N, 5.57. Found: C, 76.16; H, 5.11; N, 5.66.

Example 33: 5, 7-dimethoxy-3- (4-trifluoromethanesulfonyl phenyl) -l, 2-dihydro-2-quinoline ketone (Compound 45) Under nitrogen atmosphere, 170 mg was solubilized (0.55 mmol) of compound 8 in triflic anhydride and pyridine (8 ml, v / v) at 0 ° C. The reaction mixture was stirred at room temperature for 2 h. The medium was hydrolyzed by addition of water (10 ml) then extracted with dichloromethane (twice). The organic phase was dried over MgSO 4, then evaporated. The obtained residue was purified by chromatography on a silica column (AcOEt / CHCl2 1: 9) to give 194 mg (80%) of compound 45.

.PF 144-145 ° C (AcOEt) .IR (KBr): n 1646, 1618, 1602, 1504 cm "1 A NMR (250 MHZ, CDC13): d 3.75 (s, 3H, NCH3), 3.94 (s, 6H, CH3), 6.32 (d, ÍH, J = 2.0 Hz, HAr), 6.39 (d, ÍH, J = 2. 0 Hz, HAr), 7.30 (d, 2H, J = 8.8 Hz, HAr), 7.82 (d, 2H, J = - 8.8 Hz, HAr), 8.19 (s, ÍH, HAr). 13 C NMR (62.90 MHz, CDC13): d 30.5, 55.8, 56.0, 90.4, 93.0, 106.0, 121.0 (2), 125.3, 130.9 (3), 132.1, 138.1, 148. 9, 158.0, 161.8, 163.2.

.SM (ion spray): m / z 444 (M ++ l) EXAMPLE 34: 5, 7-dimethoxy-3- (4-acetylphenyl) -1,2-dihydro-2-quinoline ketone (Compound 46) Under nitrogen atmosphere, 200 mg (0.64 mmoles) of compound 8 in acetic anhydride and pyridine (8 ml, v / v) were solubilized at 0 ° C. The reaction mixture was stirred at room temperature for 18 hours. The medium was hydrolyzed by addition of water (10 ml) then extracted with dichloromethane (twice). The organic phase was dried over MgSO 4, then evaporated. The residue obtained was purified by chromatography on a silica column (Ac0Et / CH2Cl 1: 9) to give 165 mg (73%) of compound 46.

.PF 148-149 ° C (AcOEt / EP) IR (KBr): n 1751, 1639, 1601, 1508 cm -i A NMR (250 MHz, CDC13): d 2.31 (s, 3H, CH3), 3.72 (s, 3H, NCH3), 3.90 (s, 6H, CH3), 6.28 (d, ÍH, J = 2.0 Hz, HAr) , 6.34 (d, ÍH, J = 2.0 Hz, HAL), 7.13 (d, 2H, J = 8.8 Hz, HAr), 7.75 (d, 2H, J = 8.8 Hz, HAr), 8.15 (s,] H, HAr). 13C NMR (62.90 MHz, CDC13): d 21.3, 30.4, 55.7, 55.9, 90.3, 92.7, 106.0, 121.1 (2), 126.3, 130.1 (3), 131.4, 142.1, 150.1, 157.8, 162.0, 162.7, 169.6.

.SM (ion spray): m / z 354 (M ++ l) r- -f -t i¿a jjt £ ^? ^? ^^^^^^^^^ j ^ ggj. Analysis calculated for C20H19NO5: C, 67.98; H, 5.42; N, 3.96. Found: C, 68.23; H, 5.56; N, 3.79. EXAMPLE 35: a) N- (4-methylphenyl) -2-phenylacetamide (47) Under a nitrogen atmosphere, 1.0 g (9.3 mmoles) of 4-methylaniline in toluene (10 ml) was solubilized at 0 ° C. A solution of phenylacetyl chloride (1.25 ml, 9.4 mmol) in 20 ml of toluene was added dropwise to the medium. The reaction mixture was stirred at room temperature for 2 h, then the medium was hydrolyzed with a cold solution of sodium bicarbonate. The biphasic system was stirred vigorously for 30 minutes, then the organic phase was collected. The aqueous phase was extracted with ethyl acetate (twice). The organic phase was dried over MgSO 4, then evaporated. The residue obtained was purified by chromatography on a silica column (AcOEt / EP 3: 7) to give 1.9 g (92%) of compound 47.

S - * '. , - .. \ -M *. ** - * ».....» *, .--,,., ".. ,,«.,. t T j ^ j ^ tá .PF 119-120 ° C (AcOEt) .IR (KBr) n 3310, 1657, 1604, 1536, 1514 cm "1 A NMR (250 MHz, CDC13): d 2.28 (s, 3 H, CH 3), 3.70 (s, 2 H, CH 2), 7.06 (d, ÍH, J = 8.5 Hz, HAr), 7.25-7.38 (m, 9H , Hr) • 13 C NMR (62.90 MHZ, CDCl 3): d 21.0, 44.9, 120.1 (2), 10 127.7, 129.3 (2), 129.5 (2), 129.6 (2), 134.2, 134.7, 135.2, 169.2.

. SM (ion spray): 226 (M ++ l) . Analysis calculated for C? 5H15NO: C, 79.97; H, 6.71; N, 6.22. found: C, 80.23; H, 6.87; N, 6.11. b) 6-methyl-3-phenyl-1,2-dihydro-2-quinoline ketone (48) Under a nitrogen atmosphere and at -30 ° C, 0.41 ml (5.3 mmol, 1.5 eq) of N, N- was added dropwise. dimethylformamide at 3.3 ml (25 mmol, 7 eq) of POCI3. the medium was stirred for 15 minutes at -30 ° C, then 800 mg of amide 47 (3.5 mmoles) were added. Under stirring, the reaction mixture was brought to room temperature, then the reaction was heated at 75 ° C for 1.5 h. At the end of the reaction, this solution was poured onto stacked ice, neutralized with a 30% ammonia solution, then extracted with dichloromethane. The organic phase was dried over MgSO 4, then evaporated. The obtained residue was dissolved in 5.4 ml of glacial acetic acid and 0.2 ml of water, then the final solution was heated to reflux for 3 h. The acetic acid was evaporated. The residue was solubilized in water, neutralized with a 25% sodium hydroxide solution, then finally extracted with dichloromethane. The organic phase was dried over MgSO 4, then evaporated under reduced pressure. The residue was taken again in ethyl acetate, this operation involved the precipitation of the final product. The crystals thus obtained were filtered to give 80 mg (10%) of compound 20 48.

.PF 212-213 ° C (AcOEt) IR (KBr): n 1657, 1570 cm "25 • r "" K * "* a '" --'- - .... -.. --- .-, «., ^ - ^ -.-»., Me. . "-". ". HJ.-" - ", -, .. ....: .. -. A ...., .....- A ~ ..., .., - * - -, - .. r ^ f, fjn ^ jfafaz A NMR (250 MHZ, DMSO-d6): d 2.35 ( s, 3H, CH3), 7.25 (d, ÍH, J = 8.5 Hz, HAr), 7.33-7.48 (m, 5H, Har), 7.51 (s broad, ÍH, HAr), ^ 7.76 (d, 2H, J = 8.9 Hz, HA, 8.02 (s. H, HA), 11.87 (broad s, H, NH) .5 13 C NMR (62.90 MHz, DMSO-d6): d 20.5, 114.6, 119.5, 127.6, 127.8, 127.9 ( 2), 128.7 (2), 130.8, 131.5 (2), 136.4 (2), 137.4, 160.9.

SM (ion spray): m / z 236 (MAl) Analysis calculated for C16H? NO: C, 81.68; H, 5.57; N, 5.95. found: C, 81.78; H, 5.39; N, 6.11.

Next, results of pharmacological tests will be given which demonstrate the properties of the compounds of formula I and either alone or in association with cytotoxic agents. 1. Interaction (stimulation or inhibition of proliferation) with the generation of clonogenic cells (clonogenic test) The test used is the one described by Hamburger and 25 collaborators (Science, 1977; 197, 461-463) and Salmon and 'r ft H H fr fr fr Tr Tr Tr Tr Tr - - - - - - - - L L L L L L L L L L L L L L L L L L L L L L L L L L L L L L L L L L L L L L L L L L L L L L L L L L L L L L L L L L L L L L 的 colaboradores cell is considered clonogenic if it has the ability to proliferate and give birth to a cell colony.The "cells originating from human tumors" or cells from human tumor strains "are the cells that are the origin of the neoplastic cells that constitute a given tumor . These cells of tumor strains are responsible for the processes of observable recidivism after surgical ablation of primary tumors and are equally responsible for the formation of metastases. At the level of a tumor or a tumor cell line, these cells of clonogenic strains differ from other cells of the tumor or of the neoplastic cell line considered, due to the fact that they retain their capacity to proliferate in the absence of any solid support.

In this test, the tumor cells are placed in culture on a semi-solid support constituted by the agar. The cells alone do not need solid support for their growth (i.e. the highly tumorigenic cells called "cells of independent rooting" by MI Dawson et al., Cancer Res. 1995; 55; 4446-4451; also referred to as "clonogenic cells" in reference to "development"). clonal ") are capable of developing on such an agar-based support. Indeed, on such a medium, the normal cells - which are growing in an "adherent mode" ("cells of independent rooting" according to the terminology of M.I. Dawson) - as for example the fibroblasts, do not survive. Within a tumor cell population, grown on such a support, these are clonogenic cells (associated with an unlimited number of cell divisions and whose proliferation is called by MI Dawson "growth of independent [clonal] rooting) that are able to grow The percentage of these clonogenic cells within a tumor or a cell line varies between 0.1% and 0.001% Non-clonogenic cells (associated with a limited number of cell divisions) do not develop in this test because they need a solid support for their growth that must be done in an "adherent way" (growth of dependent attachment [adherent], according to MI Dawson et al., Cancer Res. 1995; 55: 4446-51). " The influence of compounds of formula (I) and (la) on the growth of cell colonies obtained by culturing, for example, the mammary tumor lines MCF7 and MXT and the rectal colon line HT-29 on the semi-liquid culture medium called " Soft agar "has been determined. On such a medium, alone, the clonogenic cells called by M.I. Dawson "independent (clonal) rooting cells" survive and develop. The growth of these cells in such a "non-adherent" manner testifies to their degree of tumorigenicity. Inhibition of the growth of the size of a tumor in which a larger number of clonogenic cells developed then becomes the witness of enhanced cytotoxic activity.

On the contrary, this test can also reveal that a compound is capable of inhibiting the generation / proliferation of clonogenic cells, which makes the tumor less apt to develop, thus decreasing the population of tumor cells.

The tumor cell lines studied are kept in culture in the 25 cm3 bottle boxes. Same that are then triptinized and the cells well dissociated from each other. The percentage of living cells was determined after staining of trypan blue. A cell suspension at the concentration of 5,104 to 15,104 cells / ml (depending on the cell type considered) is prepared in a 0.3% agar solution. Next, 200 μl of this suspension was seeded in 35 mm diameter petri dishes, in which 3 ml of a base strain consisting of a 0.5% agar solution was deposited. The 200 μl of cell suspension are in turn covered by 1.8 ml of a superior strain made up of a 0.3% agar solution. The boxes are then placed in an incubator 1 37 ° C, 5% C02 and 70% humidity until treatment. The latter is carried out approximately 1 to 2 hours after sowing. The compounds to be tested were prepared at a concentration 100 times higher than the desired concentration and 50 μl of these treating solutions were deposited on the upper agar layer of the corresponding boxes. In the present study, the final concentration of the products examined is 10"5, 10" 7 and 10"9 M. The boxes are then kept for 21 days in the incubator.At the 2nd day, the boxes are treated by depositing on the layer top 100 μl of a solution of MTT (3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide at 1 mg / ml prepared with RPMl 1640 medium for 3 h at 37 ° C. In the course of time, the cell colonies were fixed by adding 2 ml of formaldehyde per box.Following 24 hours of fixation, the formalin was evaporated and the number of cell colonies was colored, which were constituted of metabolically active cells, and whose surface was greater than 100 μm2 is determined, with the help of an inverted microscope. 1 «tti. • i-rUHBr i - i i - i - i m - t lr - ~ ¿* á * m * m? m ^ * * i? Mi ^^. ^^ - é imai ^^ ia ^ i & The average number of clones of clonogenic cells determined for each experimental condition studied is expressed as a percentage in relation to the average number of clones of clonogenic cells counted in the control condition exposed equal to 100%. These values, expressed as a percentage in relation to the control condition for all the products examined, are listed in Table I.

TABLE I CLONOGENIC VERIFICATION - concentrations expressed in mol. I "1 The results summarized in this table represent the mean values ± the standard error over the mean (ESM) over at least 6 domes - Control condition = 100% - (NS: p> 0.05;: p <0.05; *; p < 0.01; ***; p < 0.001). ^ yy Asi, the compounds of formulas (I) and (la), because they deal with the clonogenic behavior of the tumor: . either increase (eg: CRL 8315) - in relation to the reference situation [culture medium not added to the compounds of formula (I) or (la)] - the average number of clones of clonogenic cells come back for this fact, a greater number of tumor cells sensitive to the cytotoxic agent (since clonogenic cells are more sensitive to cytotoxic agents during their proliferation phase), or they decrease (ex: CRL 8283) the number of clonogenic cells by direct toxicity (from where, also there, the regression of the tumor). 2. Cytotoxic activity at the level of non-clonogenic cells: "MTT test" The influence of the compounds of formula (I) and (la) on non-clonogenic cells has been evaluated with the help of the MTT colorimetric test. ^ - ^^^ 'i The principle of the MTT test is based on mitochondrial reduction by the metabolically active living cells of the MTT product (3- (4-bromide, 5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium) of yellow color in a blue product, formazan. The amount of formazan thus obtained is directly proportional to the amount of living cells present in the culture well (s). This amount of formazan is determined by spectrophotometry. 10 The cell lines are maintained in monolayer culture at 37 ° C in culture boxes with a closed stopper containing MEM base medium 25 MM HEPES (Minimun Essential Medium). This medium is well adapted to the growth of a range of varied diploid or primary mammalian cells. This means is added below: - of an amount of 5% SVF (fetal calf serum) decomplemented at 56 ° C for 1 hour, 20 - 0.6 mg / ml L-glutamine, - 200 IU / ml penicillin - 200 μg / ml of streptomycin, -. 25 - 0.1 mg / ml gentamicin, *. ¿And ¿l »& > and, * AA. "" ««. TO """.." .. ", . . - .. -. . .A A. ",. . , A., .. -i. . . > . ^ ^ The 12 human cancer cell lines that have been used were obtained from the American Type Culture Collection (ATCC, Rockville, MD, USA). These 12 cell lines are: - U-373MG (ATCC code: HTB-17) and U-87MG (ATCC code: HTB-14) which are two glioblastomas, - S 1088 (ATCC code: HTB-12) which is an astrocytoma, - A549 (ATCC code: CCL-185) and A-427 (ATCC code: HTB-53) which are two non-small cell lung cancers, - HCT-15 (ATCC code: CCL-225) and LoVo (ATCC code: CCL-229) which are two colon rectal cancers, T-47D (ATCC code: HTB-133) and MCF7 (ATCC code: HTB-22) which are two breast cancers, - J82 (ATCC code: HTB-1) and T24 (ATCC code: HTB-4) which are two cancers of the bladder, . . ^ z ^^ üm- - PC-3 (ATCC code: CRL-1435) which is a cancer of the prostate.

In the experimental plane: 100μl of a cell suspension containing 20,000 to 50,000 (depending on the cell type used) cells / ml of culture medium were seeded in 96-well, flat bottom, multi-well plates and incubated at 37 ° C, under an atmosphere comprising 5% C02 and 70% humidity. After 24 hours of After incubation, the culture medium was replaced by 100 μl of freshly prepared medium containing either the different compounds to be examined at concentrations ranging from 10"5 to 10" 10 or the solvent that has been used for the solution. the products to be examined (control condition). After 72 hours of incubation under the preceding conditions, the culture medium was replaced by 100 μl of a yellow solution of MTT dissolved at a rate of 1 mg / ml in RPMl 1640. The microplates were again incubated for 3 hours at 37 ° C Then they were centrifuged for 10 minutes at 400 g. The yellowish MTT solution was removed and the blue formazan crystals formed at the cellular level were dissolved in 100 μl of DMSO. The microplates were then placed under stirring for 5 minutes. The intensity of the blue coloration that results then from the transformation of the yellow MTT blue formazan product by still living cells at the end of the experiments was quantified by electrophotometry with the aid of an apparatus of DYNANTECH IMMUNOASSAY SYSTEM type at the wavelengths of 5 570 nm and 630 nm corresponding respectively to the lengths of maximum absorbance wave of formazan and interference. A logical system integrated into the spectrophotometer calculates the average values of optical density as well as the standard deviation values (Deviation 10 Std.) And the standard error over the mean (ESM).

By way of example, the results of the average optical density, expressed as a percentage in relation to the average optical density measured in the control condition (equal to 100%), obtained at the concentration of 10%, will be given in Table II. 5 M over the 12 tumor cell lines mentioned above. twenty á mt S M u ^ ^ ürfUü-a or -? TABLE Ha o x +/- y = mean value = / - standard error control condition = 100% (NS: p> 0.05, *: p <0.05; **: p.0.01; ***: above the mean p <0.001 ) o TABLE Hb » x +/- y = mean value +/- standard error control condition = 100% (NS: p> 0.05: *: p <0.05; **: p <0.01; *** on average p <0.001 ) It seems that several of the compounds induce a slight inhibition that can reach 20-30% of the overall cellular proliferation of the tumor lines considered and that these compounds do not seem to present tissue specificity. 3. -Determination of the maximum tolerated dose (DMT): The evaluation of the maximum tolerated dose has been carried out in B6D2Fl / Jico mice from 4 to 6 weeks of age.

The compounds have been administered intraperitoneally at increasing doses with ranges of 2.5 to 160 mg / kg. The DMT value (expressed in mg / kg) was determined from observing the survival rate of the animals during a period of 14 days after a single administration of the product considered. The weight evolution of the animals is also followed during this period. When the DMT value is higher than 160 mg / kg, the DMT value was assimilated at 160 mg / kg in the absence of more data.

TABLE I II Maximum Tolerated Dose Compounds CRL DMT (mg / kg) CRL8246 (Example 1)> 160 CRL8284 (Example 2> 160 CRL8311 (Example 3)> 160 CRL8271 (Example 4)> 160 CRL8244 (Example 5) > 160 CRL8321 (Example 1] > 160 CRL8245 (Example 8; > 160 CRL8314 (Example 9)> 160 CRL8318 (Example 10)> 160 CRL8317 (Example 12; > 160 ^^ and ^ .-- .t. . i ^ .-. ^ - TABLE III (Continued) Maximum Tolerated Dose Compounds CRL DMT (mg / kg) CRL8319 (Example 14) > L60 CRL8283 (Example 15) > 160 CRL8315 (Example 16) > 160 CRL8255 (Example 17) > 160 CRL8247 (Example 18) > 160 CRL8256 (Example 19) > 160 CRL8254 (Example 20;> 160 CRL8316 (Example 21) > 160 CRL8285 (Example 22) > 160 CRL8270 (Example 23) > 160 TABLE III (Continued) Maximum Tolerated Dose Compounds CRL DMT (mg / kg) CRL8266 (Example 24) > ] 60 CRL8336 (Example 26) > ] 60 CRL8330 (Example 27) > 160 CRL8339 (Example 28) > 160 The products of this family do not present direct toxicity and can then be used in vivo at high tissue concentrations, and therefore at high doses. 4. Antitumor activity in vivo in association with a cytotoxic agent The tests were carried out on the models of: .i -i - • «!, -. i »-...-. . Mm .. ^. ... .... A zi. -..-. , ... z. ^ .i -. &tot ^. .-.- hormone-sensitive murine MXT mammary adenocarcinoma (MXT-HS), -Lymphoma P 388, in the presence or absence of cytotoxic agents such as cyclophosphamide, etoposide, doxorubicin or vincrisin.

When the DMT value of a product has been determined, its antitumor activity in vivo has been characterized at the doses of DMT / 2, DMT / 4 and DMT / 8 on the mammary adenocarcinoma model of murine origin MXT-HS and on the P388 lymphoma model. It is the dose that has presented the best antitumor activity on these different models that has been retained and used in the framework of combined treatments with cytotoxics.

In all the examples presented below regardless of the model (mammary adenocarcinoma MXT-HS or P388 lymphoma), the control condition is represented by a batch of 9 mice which have been administered for 5 consecutive weeks and at a rate of 5 administrations ( Monday, Tuesday, Wednesday, Thursday and Friday) per week a volume of 0.2 ml of physiological saline containing the solvent used to dissolve the different compounds of formula (I) and (Ia) used.

During the trials, the following were determined: i) -the survival rate of mice.

This survival index has been calculated under the form of a T / C ratio: (Number of (median (Number of mice dead days in the days surviving-mice preceding the 15 days of the treated) of the median target of treated mice from the batch of treated mice 20 ( Number of mice killed on the same day as the median number of treated mice) (Number of (median (Number of mice dead days in the surviving days- mice preceding the mea treated days) of the median target of treated rats) tones of the batch of control mice C = 10 ( Number of mice killed on the same day as the median of control mice) This ratio represents the survival time 15 means the median of mice of the batch of treated mice in relation to the average survival time of the median of mice from the batch of control mice. Thus, a molecule induces a significant increase (P <0.05) in the survival of the animals when the T / C index exceeds 20 of 130%. On the contrary it has a toxic effect when this value of T / C is less than 70%. ii) Tumor growth that is measured twice a week (Monday and Friday) the surface of the MXT-25 HS or P388 tumors grafted. This surface was calculated, effecting the product of the value of the two perpendicular major axes of the tumor. The value of these axes was determined with the help of a vernier. 4. 1. murine mammary denocarcinoma (MXT-HS) The model of hormone-sensitive murine MXT mammary adenocarcinoma (MXT-HS) grafted to B6D2Fl / JIco mice from 4 to 6 weeks of age was derived from the galactoform channels of the mammary gland (Watson C. et al., Cancer Res. 1977; 37: 3344-48).

The results obtained using compounds 1 and 20 either alone or in association with cytotoxic agents will be given by way of example.

A-Compound 1 or CRL 8264: Treatment 1 and Ibis Compound 1 was administered alone. The first injection of the product was performed on the seventh postinjection day (J7) for four consecutive weeks at a rate of 5 injections per week (Monday, Tuesday, Wednesday, Thursday and Friday) and at a dose of 20 mg / kg.

Treatment 2 Cyclophosphamide (CPA) was administered alone. The first injection of the product was carried out on the fourteenth post-transplant day (J14) for three consecutive weeks at a rate of 3 injections per week (Monday, Wednesday and Friday) and at a dose of 10 mg / kg.

Treatment 3 Compound 1 was co-administered with cyclophosphamide. In that case, the first injection of compound 1 was performed on the seventh day post-graft (J7) for four days. consecutive weeks at a rate of 5 injections per week (Monday, Tuesday, Wednesday, Thursday and Friday) at the dose of 20 mg / kg and the first injection of cyclophosphamide was performed on the fourteenth day post-graft (J14) for three weeks consecutive at a rate of 3 injections per week (Monday, Wednesday and Friday) at the dose of 10 mg / kg.

Treatment 4 The etoposide (ETO) was administered alone. The first injection of the product was carried out on the fourteenth day post- graft (J14) for three consecutive weeks at a rate of 3 injections per week (Monday, Wednesday and Friday) and at a dose of 10 mg / kg.

Treatment 5 Doxorubicin (DOX) was administered alone. The first injection of the product was performed on the fourteenth post-graft day (J14) for three consecutive weeks at a rate of 10 3 injections per week (Monday, Wednesday and Friday) and at a dose of 5 mg / kg.

Treatment 6 Compound 1 is co-administered with the etoposide. In that case, the first injection of compound 1 was performed on the seventh day post-graft (J7) for four consecutive weeks at a rate of 5 injections per week (Monday, Tuesday, Wednesday, Thursday and Friday) at the dose of 20 mg / kg and the first injection of the etoposide was performed on the fourteenth day post-graft (J14) for three consecutive weeks at a rate of 3 injections per week (Monday, Wednesday and Friday) at a dose of 10 mg / kg.

Treatment 7 Compound 1 is co-administered with doxorubicin. In that case, the first injection of compound 1 was performed on the seventh day post-graft (J7) for four consecutive weeks at a rate of 5 injections per week (Monday, Tuesday, Wednesday, Thursday and Friday) at the dose of 20 mg / kg and the first injection of adriamycin was performed on the fourteenth day post-graft (J14) for three consecutive weeks at a rate of 3 injections per week (Monday, Wednesday and Friday) at a dose of 5 mg / kg.

The results obtained for the survival time for compound 1 will be given in Tables IV and V: TABLE IV Treatment T / C (expressed in%) 1 (compound 1) 100 2 (CPA) 122 3 (compound 1 + CPA) 135 25 ^^ ¿¿¿¿¿^ ái? TABLE V Treatment T / C (expressed in Ibis (compound 1) 95 4 (ETO) 130 (DOX) 92.5 6 (Compound 1 + ETO) 150 7 (Compound 1 + DOX) 145 These results show that the co-administration of compound 1 with the cytotoxics: cyclophosphamide, etoposide or doxorubicin, significantly increases the average survival time of the median of mice of the different batches of mice treated in relation to the average survival time of the median of mice from the batch of control mice. Furthermore, this increase in the mean survival time of the median of mice from the different batches of mice treated with these co-administrations is significantly longer than that of the mice. ^^^^^^^^^^^^^ obtained with the treatments that imply these cytotoxic used alone.

The study of tumor growth has on the other hand shown the following results for compound 1. In table VI, below, decreases (-) or increases (+) of the surface of the tumors are indicated as a percentage. MXT-HS induced with the different treatments 1, 2 and 3 of example 1 in relation to the control condition at the 31st. Day after tumor grafting, ie after 19 administrations of compound 1 and 8 administrations of cyclophosphamide used or not in co-administration. At the 31st. Post-graft day, 89% of the control animals are still alive (that is 8 animals out of 9) TABLE VI Treatment Tumor surface (expressed in%) 1 (compound 1) -19.5 2 (CPA) -23.6 3 (Compound 1 + CPA) -49.6 -_- b ^ aU-A¡ AA¿¿ =. -LM The results show that the co-administration of compound 1 with cyclophosphamide induces a highly significant decrease in the growth of MXT-HS tumors more important than that induced by treatments involving compound 1 or cyclophosphamide used alone.

B-Compound 21 or CRL 8256: 10 Another example, that relating to compound 21 used alone or in association with the etoposide.

Treatment 10 15 Compound 21 was administered alone. The first injection of the product was performed on the seventh postinjection day (J7) at a rate of 5 injections per week (Monday, Tuesday, Wednesday, Thursday and Friday) for five consecutive 20 weeks and at a dose of 40 mg / kg.

Treatment 20 The etoposide (ETO) was administered alone. The first injection of the product was carried out on the seventh day post- graft (J7) at a rate of 3 injections per week (Monday, Wednesday and Friday) for three consecutive weeks and at a dose of 10 mg / kg.

Treatment 30 Compound 21 was co-administered with the etoposide. In that case, the first injection of compound 21 was performed on the seventh day post-graft (J7) at a rate of 5 injections per week (Monday, Tuesday, Wednesday, Thursday and Friday) for five consecutive weeks at the dose of 40 mg / kg and the first injection of the etoposide was performed on the seventh day post-graft (J7) at a rate of 3 injections per week (Monday, Wednesday and Friday) for 3 consecutive weeks at a dose of 10 mg / kg.

Table VII reports the results of the survival time obtained with compound 21. twenty TABLE VII Treatment (T / C (expressed in%) (compound 21) 110 (ETO) 124 (compound 21 + ETO) 138 These results show that the co-administration of compound 21 with the etoposide induces a significant increase in the average survival time of the median of mice of the batch of mice treated in relation to the average survival time of the median of mice from the batch of mice control. Furthermore, this increase in the average survival time of the median of mice from the batch of mice treated with this co-administration is significantly longer than that obtained with treatments involving this 2-quinolone or this cytotoxic used alone. 4. 2. Linforna P388: CDF1 mice 4 to 6 weeks old were grafted with a piece of P388 tumor (which came from a bank of tumors preserved in the laboratory) subcutaneously on the right flank on day JO. In order to place ourselves in a situation close to clinical reality, we wait for the 5th. Post-graft day (J5) before starting treatment. This, since after this lapse of time subcutaneous P388 tumors are palpable.

By way of example, the results obtained with compounds 1 (CRL 8246) and 20 (CRL 8247) alone or in association with vincrinstine are reported below.

Treatment 1 Compound 1 was administered alone. The first injection of the product was performed on the fifth post-transplant day (J5) at a rate of 5 injections per week (Monday, Tuesday, Wednesday, Thursday and Friday) for five consecutive weeks and at a dose of 40 mg / kg.

Treatment 2 Compound 20 was administered alone. The first injection of the product was performed on the fifth day post-graft (J5) at a rate of 5 injections per week (Monday, Tuesday, Wednesday, Thursday and Friday) for five consecutive weeks and at a dose of 40 mg / kg.

Treatment 3 Vincristine (VCR) was administered alone. The first injection of the product was carried out on the fifth post-transplant day (J5) at a rate of 3 injections per week (Monday, Wednesday and Friday) for three consecutive weeks and at a dose of 0.63 mg / kg.

Treatment 4 Compound 1 is co-administered with vincristine.

In that case, the first injection of compound CRL8246 was performed on the fifth day post-graft (J5) at a rate of 5 injections per week (Monday, Tuesday, Wednesday, Thursday and Friday) for five consecutive weeks at the dose of 40 mg / kg and the first injection of vincristine was performed on the fifth day post-graft (J5) at a rate of 3 injections per week (Monday, Wednesday and Friday) for three consecutive weeks at a dose of 0.63 mg / kg.

- - • - • - * Treatment 5 Compound 20 was co-administered with vmcristin. In that case, the first injection of compound CRL 8247 was performed on the fifth day post-graft (J5) at a rate of 5 injections per week (Monday, Tuesday, Wednesday, Thursday and Friday) for five consecutive weeks at the dose of 40 mg / kg and the first injection of vincristine was performed on the fifth day post-graft (J5) at a rate of 3 injections per week (Monday, Wednesday and Friday) for three consecutive weeks at a dose of 0.63 mg / kg.

In Table IX the results obtained with the treatments 1 to 5 mentioned below are presented, 15 on the survival time of the mice. twenty ^ ¡¡¡¡¡¡¡¡¡¡^^^ ¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡TABLE IX Treatment T / C (expressed in%) 1 (compound 1) 120 2 (compound 20) 125 3 (VCR) 122 10 4 (compound 1 + VCR) 144 (compound 20 + VCR) 164 These results show that the co-administration of compounds 1 and 20 with vincristine increases in a highly significant way the average survival time of the median of mice of the different batches of mice treated in this way in relation to the average survival time 20 of the mice. the median number of mice in the batch of control mice. In addition, this increase in the mean survival time of the median of mice from the different batches of mice treated with these administrations is significantly longer than that obtained with treatments involving - ^ -ttrft 'lrililWfr'iÉriíiM.i, - »t -. -4 ,,. «, ...... ^ ....... ... ...i. ^ .......,, .. ^ ",. ..., ..,, "A, ^. . íik? & ^ ti? ,, these two compounds 1 and 20 or the vincristina used alone.

Examples of mode of use of the compounds of formula (I) and (a) in mono or polychemotherapy protocols by cytotoxic agents will be given below. In these protocols, the compounds of formula (I) and (la) will be referred to for simplicity, "2- quinolone". 10 A. Solid tumors 1 ° / Lung cancers 1.1. or small cell (advanced state) to the recommended protocol (T. Le Chevalier et al., J. Clin. Oncol., 1994; 12: 360-367) were added intravenous infusions of a 2-quinolone: 20 u¿m á ^ m áa áHiiÉu iaiÉÉá-. á-ki-tt-tt¿ ^ iA £ 4 ^ ri¡MiÍÉÍli? dose via days .2-quinolone 200-2000 mg / m / day i.v. Ji, Jb, J15, or 5-50 mg / kg / day J; Ac and JSÓ 5 perfusion of lh .navelbina 30 mg / m2 / day i.v. Ji, J8, J15, . Scisplatin 120 mg / pr i.v. Ji and J2q This healing is repeated 8 times. 1. 2. From small cells (advanced state) 15 - to the recommended CAV or VAC protocol (B. J. Roth et al., J. Clin. Oncol. 1992; 10: 282-291) were added the 2-quinolone infusions: twenty tíKl m? ttáisMlit i read '' 11 thymus i, t. . .---- ^ i -------- .., -...-.-----, .- ,. . ... .. ... ... ¡, t tffifcjflgffljfty dose via days .2-quinolone 200-2000 mg / m2 / day i.v. J: or 5-50 mg / kg / day 5 perfusion of lh Cyclophosphamide 1000 mg / m2 in i.v. Ji bolus .doxorubicin 40 to 50 mg / m "i.v. .vincristine 1 to 1.4 mg / m2 i.v. Ji in bolus (max 2 mg) 15 This cure is repeated 6 times every 21 days. to the recommended protocol Pt-E (B "J. Roth et al., J. Clin. Oncol. 1992; 10: 282-291) 2-quinolone infusions were added dose via days , 2-quinolone 200-2000 mg / m2 / day i.v, J1-J5 or 5-50 mg / kg / day 1-hour infusion cisplatin 20 mg / m2 / day 1. v, Jl - J5 perfusion from 20 to 60 minutes etoposide 80 mg / m2 / day 1. v. Ji -J5 60 minute infusion Each cycle is repeated every 21 days and the cure includes 6 cycles. 1. 3. Bronchial cancer not of small cells, locally advanced or etastatic: . onochemotherapy: dose via days .2-quinolone 200-2000 mg / m2 / day i. v. Ji, Js, Jis or 5-50 mg / kg / day then 1 1-hour infusion of resting .gemcitabine 1000 mg / m / day i.v. J?, J8, Ji5 perfusion of then 1 se- 0.5 hour mana of rest the healing may consist of the repetition of this 4-week cycle. .ssociation of gemcitabine / cisplatin: dose via days .2-quinolone 200-2000 mg / m2 / day i.v, JiAsAßAis or 5-50 mg / kg / day 1-hour infusion dose via days .gemcitabine 1000 mg / m "/ day i.v. Ji, Je, J-s perfusion 0.5 hour .cisplatin 20 mg / m2 / day i.v. Jx perfusion of 20-60 minutes 10 the healing consisting of the repetition of this cycle every 21 days. 2"/ Breast cancers 15-CMF protocol in adjuvant treatment of operable breast cancer (G. Bonnadonna et al., N. Engl. J. Med., 1976; 294: 405-410): twenty dose via days .2-quinolone 200-2000 mg / m2 / day i.v. Ji aJi- or 5-50 mg / kg / day 5 perfusion of 1 h cyclophosphamide 100 mg / m2 / day oral Ji to Ji- .metotrexate 40 mg / m2 i.v. Ji and J8 10 in bolus -FU 600 mg / m2 i.v. Ji and J8 each cycle was repeated every 28 days and healing 15 consisted of 6 cycles. -protocol AC (B. Fisher et al, J. Clin Oncol, 1990; 8: 1483-1496) in adjuvant treatment: twenty - atja * a * ate '-? ^ Ai - é- dose via dias 2-quinolone 200-2000 mg / m2 / day i.v. J: or 5-50 mg / kg / day 1-hour infusion .doxorubicin 60 mg / m- i. v, Ji in bolus . cyclophosphamide 600 mg / m "i.v. Ji in bolus each cycle is repeated every 21 days and the cure consists of 4 cycles.

- Breast cancers with metastasis: -in the FAC protocol (A. U. Buzdar et al., Cancer 1981; 47: 2537-2542) and its different adaptations, 2-quinolone infusions are added according to the following (non-limiting) scheme: d -? - M-É-ilÍMÍl ---- l dose vi ci days . 2-quinolone 200-2000 mg / m / day i. v. J1-J5 and or 5-50 mg / kg / day c-Jic or 5 perfusion of 1 h J1-J5 . 5-FU 500 mg / m2 / day i. v. Ji and J8 or J: Y J .doxorubicin 50 mg / m2 i.v. J or Ji and in bolus Je cyclophosphamide 500 mg / m "i.v. Ji in bolus u 15 oral Ji each cycle is repeated every 3 weeks until the diagnosis of a new progression of the disease twenty - . 20 -in the CAF protocol (G. Falkson et al., Cancer 1985; 56: 219-224): dose via days .2-quinolone 200-2000 mg / m2 / day i.v. J: at J14 or 5-50 mg / kg / day 1-hour infusion cyclophosphamide 100 mg / m2 / day oral Ji a n .doxorubicin 30 mg / m2 i.v. J and J8 in bolus .5-FU 500 mg / m2 i.v. Ji and J8 in bolus each cycle is repeated every 28 days until diagnosis of a new progression of the disease. -in the CMF protocol: dose via days .2-quinolone 200-2000 mg / m "/ day i.v. J1-J5 and or 5-50 mg / kg / day J8-Ji2 perfusion of 1 h dose via days cyclosphosphamide 600 mg / pr / day i.v. J: a J = in bolus 5 .metotrexate 40 mg / m2 / day i.v. Ji and J8 in bolus , 5-FU 600 mg / m2 / day i.v. Jx and Jg 10 in bolus This cycle is repeated every 3 to 5 weeks and the cure consists of 6 cycles. fifteen - . 15 -in the CMF-VP protocol: dose via days .2-quinolone 200-2000 mg / m2 / day i.v. J? ~ J5 20 or 5-50 mg / kg / day J8-Ji2 1-hour infusion J15-J19 cyclophosphamide 22 to 2.5 mg / kg / day oral daily 25 --tae? m rztí A. ^ ¿^ ^^^^ ggjigj ^ ag ^ gjfcfe dose via days .metotrexate 25 to 50 mg / m "/ day i.v. J?, J8, J-5 .5-FU 300 to 500 mg / m / day i.v. J?, J8, Ji5 / J22 .vincristine 0.6 to 1.2 mg / m2 / day i.v. J?, J8, J? S, 10 J2: .prednisone 30 mg / m2 / day oral from Ji to Jio This healing is repeated every 4 weeks. fifteen -in the FEC protocol: Dosage via 20 .2-quinolone days 200-2000 mg / m2 / day i.v. J1-J5 and 1-hour infusion jgg jaj j ^ -. ** - _ .. ssfestt ^ .. dose via days .5-FU 600 mg / m2 / day i.v. Ji and, .epirubicin 50 mg / m "i.v. J: Cyclophosphamide 600 mg / m "i.v.

This healing is repeated every 3 weeks. -in the MMC-VBC protocol (C. Brambilla et al., Tumori, 1989; 75: 141-144) dose via days .2-quinolone 200-2000 mg / m2 / day i.v. J1-J5 and or 5-50 mg / kg / day J15-J19 perfusion for 1 h .mitomycin C 10 mg / m "i.v. Ji in bolus . vinblastine 50 mg / m2 / day i. v. Ji and J15 in bolus This treatment is repeated every 28 days until diagnosis of disease progression. -in the NFL protocol (S.E. Jones et al., J. 5 Clin. Oncol. 1991: 9: 1736-1739): dose via days .2-quinolone 200-2000 mg / m / day i.v. J? -Js 10 or 5-50 mg / kg / day 1-hour infusion mitoxantrone 10 mg / m2 i.v. Ji in bolus 15 .5-FU 1000 mg / m2 in i.v. J? -J3 24-hour infusion leucovopna 100 mg / m "i.v. Ji in bolus Healing consists of two cycles spaced out in 21 days then needs an evaluation. 25 ^ j ^ ¡g ^ g - £ á & z, .. - 2-quinolone infusions may also be associated with the treatment of breast cancers with metastases when a taxoid is used, for example: -with paclitaxel (F.A. Holmes et al., J. Natl.

Cancer Inst. 1991; 83: 1797-1805) in the treatment of forms with metastases eventually resistant to anthracyclines: dose via days .2-quinolone 200-2000 mg / m2 / day i.v. J? ~ J5 or 5-50 mg / kg / day 1-hour infusion paclitaxel 175 mg / m ~ i.v. Jx in perfusion from 3 to 24 hours This cycle is repeated every 21 days until a new progression of the disease is diagnosed. -with docetaxel (C.A. Hudis et al., J. Clin.

Oncol. nineteen ninety six; 14: 58-65), in locally advanced or metastatic breast cancer, resistant or relapsing after cytotoxic chemotherapy (which has contained an anthracycline) or relapse in the course of adjuvant treatment: dose via days .2-quinolone 200-2000 mg / mVday i.v. J1-J5 or 5-50 mg / kg / day 1-hour infusion .docetaxel 100 mg / m "i.v. Ji or 60-100 mg / m2 in perfusion of 1 hour (or 24 hours) This cycle is repeated every 21 days for a cure of 2 cycles or until the onset of a progression of the disease. -in the protocols of dose intensification, which associates a transplant of autologous medullary cells and cells of peripheral blood strains, in consolidation of the treatment of first intention, for example: . . . * A > -. ^ ^^^^^^^^ ^^^^^^^^^^^^^^^^^^ & ^^^^^ - CPB protocol (WP Peters and collaborators, J. Clin. Oncol., 1993; 11: 132-1143), in which perfusion i.v. of strains cells that take place on days J-i, JO and Jl: dose via days .2-quinolone 200-2000 mg / m / day i.v. J_6-J-? or 5-50 mg / kg / day 10 perfusion of 1 h cyclophosphamide 1875 mg / m "i.v. J_e to J_4 in 1-hour infusion 15 scisplatin 55 mg / m2 / day i.v. J-6 to J_ in 24-hour continuous infusion 20, carmustine 600 mg / m" / day i. v. J- (BCNU) in 2-hour infusion g ^^ f & ^ ^^^^ jj ^ jfe ^^^^-CTCb protocol (K. Antman et al, J. Clin Oncol 1992, 10: 102-110), in which the perfusion í.v . of strain cells that take place on JO day. dose via days 2-quinolone 200-2000 mg / m2 / day i.v. J-7-J-1 or 5-50 mg / kg / day 1-hour infusion cyclophosphamide 1500 mg / m "i.v, J-7 to J- in 24-hour continuous infusion. . thiotepa 125 mg / m2 in i.v. J-7 to J-3 continuous infusion 24 hours (4 doses) . Carboplatin 200 mg / m2 in i. v J-7 to J-2 continuous 24-hour infusion (4 doses) and ^^^ - CTM protocol (L. E. Da on et al., J. Clin. Oncol. 1989; 7: 560-571 and I. C. Henderson et al.

J. Cellular Biochem. 1994 (Suppl 18B): 95) in which perfusion i.v. of hematopoietic stem cells that take place on J- day: dose via days .2-quinolone 200-2000 mg / m2 / day i.v. J-6-J_? or 5-50 mg / kg / day 1-hour infusion cyclophosphamide 1500 mg / m "i.v. J_D to J_3 in 1 hour infusion. . thiotepa 150 mg / m "in i.v. J_6 to J-3 2-hour infusion mitoxantrone 10-15 mg / pr in i.v. J_6 to J_3 1 hour infusion 3"/ Gynecological cancers 3. 1. Ovarian cancer -for the treatment of ovarian carcinomas, in particular metastatic: i) PAC protocol (G. A. Omura et al., J. Clin. Oncol. 1989; 7: 457-465): 2-quinolone infusions were administered according to the following scheme: dose via days .2-quinolone 200-2000 mg / m "/ day i.v. J1-J5 or 5-50 mg / kg / day 1-hour infusion .cisplatin 50 mg / m2 (or 40- i.v. Jx 90 mg / m ") perfusion for 1 to 2 hours .doxorubicin 50 mg / m "bolus i.v. Ji (or 30 to 50 mg / m Ajt? u This dose via days cyclophosphamide 1000 mg / m2 per- i.v. Ji fusion of 1 to 2 hours (or 200 to 600 mg / m2) This cycle is repeated every 21 to 28 days and the cure consists of 8 cycles. ii) Altretamine protocol, according to A. Marieta et al (Gynecol Oncol 1990, 36: 93-96): dose via days .2-quinolone 200-2000 mg / m "/ day i.v. J1-J5 or 5-50 mg / kg / day J8-Ji2 1-hour infusion .altretamine 200 mg / m / day J1-J15 divided into 4 oral doses the healing consists of two cycles, with 28 days of interval. - »" - "* ii) paclitaxel protocol: 2-quinolones can be added to the paclitaxel protocol that has been described by W.P. Mc Guire et al (Ann.Inter.Med. 1989; 111: 273-279): dose via days .2-quinolone 200-2000 mg / m / day i. v. J? ~ J? or 5-50 mg / kg / day 1-hour infusion .paclitaxel 135 mg / m "perfusion of 3 hours or 24 hours i.v.

Healing consists of two of these cycles, at 28-day intervals (with evaluation from the beginning). -for the treatment of metastatic and refractory ovarian carcinomas, 2-quinolones can be added to the protocol of second intention, based on topotecan: dose via days .2-quinolone 200-2000 mg / m / day i. v. J1-J5 or 5-50 mg / kg / day 1-hour infusion .topotecano 1.5 mg / m / day perfusion 0.5 hours i.v. J1-J5 10 the healing consists of two cycles, at intervals of 21 days (with evaluation from the beginning) according to A.P. Kudelka et al. (J. Clin 15 Oncol., 1996; 14: 1552-1557). 3. 2. Oblong trous umores: -in low risk patients, 2-quinolones may be associated to the protocol described by H. Takamizawa et al. (Semin. Surg. Oncol. 1987; 3: 36-44): ^^^^^^^ J ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ dose via days , 2-quinolone 200-2000 mg / m2 / day i.v. J, -J5 or 5-50 mg / kg / day 1-hour infusion .metotrexate 20 mg / day i.m. J1-J5 (MTX) .dactinomycin 0.5 mg / day in i.v. J1-J5 bolus (MTX-DATC protocol). 3. 3. Cancers of the uterus: -the 2-quinolones can also be associated with the CAV protocol (or VAC) according to the following scheme: dose via days .2-quinolone 200-2000 mg / m2 / day i.v. J1-J3 or 5-50 mg / kg / day 1-hour infusion - - .. z .... "> * -_ ,. z. . . . ... ... ? . ,,. . t Utü &MLAt * .. dose via days cyclophosphamide 750-1200 mg / m2 i.v. J_ in perfusion .doxorubicin 45-50 mg / m2 i.v. Ji .vincristine 1.4 mg / m2 i.v. J ± Healing consists of the repetition of this cycle every day. dose via dias .2-quinolone 200-2000 mg / m2 / day i.v. J1-J5 or 5-50 mg / kg / day 1-hour infusion . fluorouracil 600 mg / m ~ / day i.v. JiAs (5-FU) .doxorubicin 30 mg / m 'i.v. Ji cisplatin 75 mg / m2 l.V, healing consists of the repetition of this cycle every 28 days.

"/ Testicular cancers -the 2-quinolones can also be associated with rotocoluses of cancer of the testicles: BEP Protocol: dose via days .2-quinolone 200-2000 mg / m2 / day i.v. J1-J5 or 5-50 mg / kg / day 1-hour infusion .bleomycin 30 q / m in i.v. Ji perfusion .eposited 100 mg / m2 / day i.v. J1-J5 in perfusion .cisplatin 20 mg / m2 / day i.v. J1-J5 - ^ t i t ^^^^ - ^ á h? Iti healing consists of 3 cycles at a rate of one cycle every 21 days.

"/ Bladder cancers -the 2-quinolones can be associated with the CISCA2 protocol (also called PAC) dose via days .2-quinolone 200-2000 mg / m2 / day i.v. J1-J5 or 5-50 mg / kg / day 1-hour infusion .cisplatin 50 mg / m "i.v. cyclosphosphamide 600 mg / m "i.v. Ji in perfusion .doxorubicin 75 mg / m "i.v. Ji in perfusion the cycle is repeated every 3 weeks. -in the MVAC protocol (according to CN Stemberg and I., J. Urol. 1988; 139: 461-469): dose via days .2-quinolone 200-2000 mg / m / day i.v. J1-J3 or 5-50 mg / kg / day J15-J18 perfusion for 1 h J22-J25 .metotrexate 30 mg / m "/ bolus i.v. J-./J15. vinblastine 3 mg / m "i.v. J; 0J2, .doxorubicin 30 mg / m2 i.v. J2 in bolus .cisplatin 70-100 mg / m "i.v. Ji or J2 perfusion 1 hour 6 ° / naso-pharyngeal carcinoma / cancers of the head and neck -The 2-quinolones may be validly associated with the polychemotherapy protocols used in the treatment of these cancers: 6. 1. Naso-pharyngeal cancers: -protocol ABVD: dose via. days 10 2-quinolone 200-2000 mg / m2 / day i. v. J.- J3 perfusion of 1 hr Jl5 ~ Jl7 fifteen . doxorubicin 30 mg / m / day i. v. Ji and J8 or J15 .bleomycin 10 mg / m2 / day. v Ji and Je or J15 20 .vinblastine 6 mg / m "/ day i.v Ji and J8 or Jl5 , dacarbazine 200 mg / m2 / day i. v Ji and JT Ó Jl5 ü-üÉ-i & ^ ia - = - 3is & Healing consists of 1 to 6 cycles at a rate of 1 cycle every 4 weeks. 6. 2. Cancers of the head and neck with metastases -in the Pt-FU protocol (eg: for pharyngeal cancer): according to the DVAL Study Group (New Engl. J.M. 1991; 324: 1685-1690): 10 doses via days .2-quinolone 200-2000 mg / m2 / day i.v. J1-J5 or 5-50 mg / kg / day 15 perfusion of 1 h .cisplatin 100 mg / m2 i.v. Ji perfusion of 1 hour 20. f luorouracil 1000 mg / m2 / day i.v. J1-J5 (5-FU) continuous perfusion The cure consists of two cycles, at a rate of 1 cycle every 3 weeks. 7"/ Soft tissue sarcomas -The 2-quinolones can be introduced into a protocol such as the CYVADIC protocol: -according to H.M. Pinedo et al. (Cancer 1984; 53; 1825): dose via days .2-quinolone 200-2000 mg / m2 / day i.v. J1-J5 perfusion of 1 h J15-J17 . cyclophospide amide 500 mg / m2 in bolus i.v. J2 (Cy) .vincristine 1.5 mg / m2 / day i.v. J?, J8 / (V) in bolus J? 5 .doxorubicin (A) 50 mg / m2 bolus i.v. J2 é hit r ^ fcJttÉMÉiÉÉi dose via days .dacarbazine 250 mg / m2 / day i.v. J: -J; Healing consists in the repetition of this cycle every 4 weeks, first for 2 cycles. 8"/ Cancer of the hormone-refractory prostate, with metastasis 10 in the VBL-estramustine protocol, according to G. R. Hudis et al. (J. Clin. Oncol. 1992; 10; 1754: 1761): doses via days .2-quinolone 200-2000 mg / m / day i.v. J? ~ J3, or 5-50 mg / kg / day J5-J10, perfusion for 1 h J15-J17, 20 J22-J24, Jt? I * ¡ii¡ "fr" * "* - * ^ '^" 1-' '' - "'" "' - • '' • '' - ™ - ** - - - - < '' - - - "" • '- dose via days . vinblastine 4 mg / nr / day in bolus i. v. J ?, J8, J 9. J36 .stramustine 200 mg / m2 in daily oral tid, for 6 weeks a course of treatment for 6 weeks and that is followed by two weeks of free interval. 9 ° / Germ cell cancers i) for favorable prognosis tumors: Pt-E protocol, according to G. J. Bosi et al (J. Clin. Oncol. 1988; 6: 1231-1238): dose via days .2-quinolone 200-2000 mg / m "/ day i.v. J1-J5 or 5-50 mg / kg / day perfusion of 1 h dose via days .cisplatin 20 mg / m2 / day i.v. J: ~ Js (Pt) perfusion of 20 to 60 minutes . atoposide 100 mg / m / day i. v. J1-J5 (E) 1 hour perfusion The corresponding cure consists of 4 cycles, at a rate of 1 cycle every 21 or 28 days. ii) for tumors with metastases: - PEB protocol, according to S.D. Williams et al. (N. Engl. J. Med. 1987; 316: 1435-1440): dose via days .2-quinolone 200-2000 mg / m2 / day i.v. J1-J5, or 5-50 mg / kg / day J9-J11, perfusion of 1 h Jie-Jie, dose via days .cisplatin (P) 20 mg / m2 / day i.v. J1-J5 perfusion from 20 to 60 minutes .etoposide (E) 100 mg / m / day i.v. J / J9A10 .bleomycin (B) 30U (or mg) / day i.v. J1-J5 in bolus The cure consists of 4 cycles, at a rate of 1 cycle every 21 days.

"/ Kidney cancers - metastatic renal carcinoma: the 2 quinolones can be introduced into the protocol described by M. J. Wilkinson et al. (Cancer 1993; 71: 3601-3604): dose via days .2-quinolone 200-2000 mg / pr / day i.v. J1-J5, or 5-50 mg / kg / day J8-J? S infusion of 1 h dose via days . floxuridine 0.075 mg / kg / day i.v. J: -J? -, Healing consists of two cycles spaced 28 days apart. -nefroblastoma: 2-quinolones can be introduced in the DAVE protocol: dose via days .2-quinolone 200-2000 mg / m2 / day i.v. J1-J3, or 5-50 mg / kg / day J8-J or 1-hour infusion .dactinomycin 0.6 mg / m2 / day i.v. J?, J8 .doxorubicin 30 mg / m2 / day i.v. Ji, J8 Cyclophosphamide 200 mg / m2 / day i.v. J?, J8 perfusion of 1 h at the rate of one cycle every 3 to 4 weeks. 11th / Digestive tract cancers ^^ -an- ^ j- 11.1 Cancers of the esophagus: -The 2-quinolones can be introduced in the FAP protocol according to: dose via days .2-quinolone 200-2000 mg / m / day i. v. J? ~ J3, or 5-50 mg / kg / day J8-J or 1-hour infusion .5-fluorouracil 600 mg / m2 i.v. J?, J8 (5-FU) 15 .doxorubicin 30 mg / m2 i.v. Ji .cisplatin 75 mg / m2 i.v. Ji this cycle is repeated every 3 to 4 weeks. 11. 2 Stomach cancers -in advanced gastric carcinomas and / or with 25 metastases: - EAP protocol (according to P. Presser et al., J. Clin. Oncol. 1989; 7: 1310): dose via days , 2-quinolone 200-2000 mg / m2 / day i.v. J? -J3, or 5-50 mg / kg / day Js-Jio perfusion of 1 h .etoposide 120 mg / m2 / day i.v. J3, J4, perfusion of J5 or J4 1 hour -Je .doxorubicin 20 mg / m2 / day i.v. J?, J7 .cisplatin 40 mg / m "/ day i.v. J2, J8 perfusion 1 hour at a rate of 1 cycle every 28 days.

- FAMtx protocol: according to J.A. Wils et al. (J. Clin. Oncol., 1991; 89: 827): ^ M ét? TmtM É ^ ^ É - ^^ dose via days .2-quinolone 200-2000 mg / m2 / day i. v. J.-J3, or 5-50 mg / kg / day 1-hour infusion .5-fluorouracil 1500 mg / m2 i.v. Ji (5-FU) 1 hour after methotrexate .doxorubicin 30 mg / m2 in bolus i.v. Ji5 (A) .metotrexate 1500 mg / m "i.v. Ji (Mtx) Healing consists first of two cycles, with spaces of 28 days. -in certain diseases, this protocol or its variant (the epirubicin that replaces the doxorubicin) may be used according to the following scheme: dose viéi days , 2-quinolone 200-2000 mg / m2 / day i.v. J1-J3, or 5-50 mg / kg / day 1-hour infusion -fluorouracil 1500 mg / m "i .. Jz; 5-FU) . doxorubicin 30 mg / m "in bolus i. v. J? = FAMT (A) or , epirubicin (A) 60 mg / m2 in bolus i. v. J? = FEMTv .metotrexate 1500 mg / m2 1. v. (for perfusion before 5-FU) leucovorin 15 mg / m "/ day 1. v. J2-J. 12"/ Colon-rectal cancers -the 2-quinolones can be introduced in the adjuvant treatment protocol FU-levamizol colon-rectal cancer (according to C.G. Moertel and J ^^^^^^ 2 * fer and collaborators, N. Engl. J. Med. 1990; 322: 352) dose via days , 2-quinolone 200-2000 mg / m / day i. v. J1-J5, or 5-50 mg / kg / day J -J3Í 1-hour infusion -fluorouracil 450 mg / m2 / day i. v. Ji-J5 10; 5-FU) in bolus -fluorouracil 450 mg / m "in bolus i.v. J29: 5-FU) fifteen . levamizol 50 mg oral tid 3 days / week, every 2a. Week the bolus treatment for 5-FU is repeated every 20 weeks after the induction phase J1-J5, for .52 weeks; this for a 2-quinolone that is repeated in the same rhythm, the day of the 5-FU bolus, then the next 2 days. -. 25 -for the treatment of colon-rectal cancer, -lili • TÍTMfSa, -i8 - * "» - ^ ¡^ fcj ^ S SJfot t ^ refractory to treatment by 5-fluorouracil (5-FU) and with metastasis: -according to M.L. Rothenberg et al (J. Clin. Oncol., 1996; 14: 1128-1135): dose via days . 2-quinolone 200-2000 mg / m2 / day i. v. J? ~ J3, J8- Jio, or 5-50 mg / kg / day J15-J17 A 2 perfusion of 1 h -J? . . irinotecan 125 mg / m2 / day i. v. Jx, J8, J? 5, J- Healing consists of two cycles, spaced by 42 days 13 ° / Kaposi sarcomas -the 2-quinolones can be associated to the two protocols that use anthracyclines formulated in liposomes: i) protocol described by P.S. Gill et al (J. j¿ ^^ Sg? sggggfe.

Clin. Oncol. nineteen ninety five; 13: 996-1003) and C.A. Presant et al. (Lancet 1993; 341: 1242-1243): Dosage via 5 .2-quinolone days 200-2000 mg / m2 / day i.v. J? ~ J3 / ó 5-50 mg / kg / day J? S_Ji7 1-hour infusion daunorubicma liposomática 20 mg / nr / day i.v. J?, J? S 1 hour infusion the healing consists of two cycles repeated at 28 days of interval before evaluating the effects. ii) protocol of M. Harrison et al (J. Clin. Oncol. 1995; 13: 914-920): 20 doses via days .2-quinolone 200-2000 mg / m2 / day i.v. J? -J3 or 5-50 mg / kg / day 25 perfusion of 1 h »-ia --- &__- ¿3¿ - A ^^ .. .- .. - .yztt- ^ y ^ .-. ^ -.- -«. -, - ^ ^^ dose via days .doxorubicin 20 mg / m2 / day i.v. Liposomatic perfusion 30 minutes Healing consists of two repeated cycles at 28 days interval before evaluating the effects. 14 ° / Metastatic melanomas -the 2-quinolones can also be incorporated into the combined treatment protocols of malignant metastatic melanomas: - DTIC / TAM protocol: according to G. Cocconi et al. (N. J. Med. 1992; 327: 516), the cure consists of the repetition of 4 cycles, at a rate of 1 cycle every 21 days, according to the following scheme: dose via days 2-quinolone 200-2000 mg / m2 / day i. v. J 1i - "JJ 5 or 5-50 mg / kg / day 1-hour infusion • ÉátaAAiáhÉMa? MiwaitfcMdi, - ---- - "- - and --'--" lÉfTr dose via days .carbazine 250 mg / m / day i.v. J: ~ Js (DTIC) perfusion [15 to 30 minutes if it is with a central catheter] or [30 minutes if per peripheral perfusion in 250 ml] tamoxifen 20 mg / m2 / day oral Ji 1 - J «J5 (TAM) The cure consists of 4 cycles at a rate of 1 cycle every 21 days. 15 15"/ neuroendocrine carcinoma -the 2-quinolones can be associated to the protocol described by C.G. Moertel et al. (Cancer 1991; 68: 227): -.X..A ^ A ^. * U ^ S ^ i,. ^. ^ -. A -Pt-E protocol: dose via days .2-quinolone 200-2000 mg / m / day i. v. J? -J3 or 5-50 mg / kg / day 1-hour infusion . etoposide 130 mg / m2 / day i. v. J? -J3 perfusion of 1 hour . cisplatin 45 mg / m2 / day i. v. J2A3 1 hour infusion The cure consists of 2 repeated cycles every 28 days. 16 ° / Cancer of the pancreas twenty - . 20 -adeno-advanced pancreatic carcinoma: the 2-quinolones may be associated with the treatment by gemcitabine, according to the protocol of M. Moore et al. (Proc. Soc. Clin. Oncol. 1995; 14: 473): dose via days 2-quinolone 200-2000 mg / m2 / day i. v. Jx-J3, Js-Jic or 5-50 mg / kg / day J15. A22 J2 perfusion 1 hr J36, J43; J57 , gemtamycin 1000 mg / m2 i.v. J, J8, J15; J2; perfusion of 0.5 J 9 J36, J43, then once / week for 3 weeks, then 1 week of rest and evaluation B.Oco-hematology 1"/ Acute leukemia in adults 1. 1. acute lymphoblastic leukemia: 1. 1. Linker protocol ^ ykld ^ 2-quinolones can be added to the protocols of Linker-induction chemotherapy and consolidation chemotherapy. (see C.A. Linker et al., Blood 1987; 1242-1248 and C.A. Linker et al. Blood 1991; 78: 2814-2822) according to the following schemes: i) induction chemotherapy: dose via days 10, 2-quinolone 200-2000 mg / m / day i. v. J1-J5, Js-Jn or 5-50 mg / kg / day J15-J19 perfusion for 1 h fifteen . daunorubicin 50 mg / m2 in bolus i.v. J?, J2, J3 every 24 hours (30 mg / m2 in patients over 50 years) .vincristine 2 mg in bolus i. V. Jl, Jy, Jl £ J22 .prednisone 60 mg / m2 / day oral J1-J2.

L-asparginase 6000 U / m2 i.m. J17-J 2E - ^ & - * ^ jM * ll) ÍWlllÍíllí1ifif | - "* - '• * tt t * -t j ^^^^^ ^^^^^ gf ¿^ ^^ * ^ ii) chemotherapy?. of consolidation (regime A) dose via days 2-quinolone 200-2000 mg / m2 / day i.v. J1-J5, Je-Ji: or 5-50 mg / kg / day 1-hour infusion .daunorubicin 50 mg / m "in bolus i.v. J?, J2 every 24 hours .vincristine 2 mg in bolus i.? . Jl, Je .prednisone 60 mg / pr / day oral J? -Ji4 divided into 3 doses , L-asparginase 12000 U / pr i.m. J2, J, J7 Jg and J? 4 The consolidation cure A comprises 4 consecutive cycles such as that described below = cycles 1, 3, 5 and 7. ? ^ '^^^^^^ y ^ ^ -H-- ygj ET TU, l ^ AA ^ l- ai-jel ------ iii) consolidation chemotherapy (regéiaenes B and C): The regimes described below correspond to consolidation cycles 2, 4, 6 and 8 (regimen B) and 9 5 (regimen C), described by C. A. Linker et al .: B regime Dosage via days 10, 2-quinolone 200-2000 mg / m2 / day i.v. J1-J5, Js-Jn or 5-50 mg / kg / day 1-hour infusion .Ara-C 300 mg / m2 i.v. J1, J4, J8, Jll teniposide 165 mg / m 'i.v. J1, J4, J8, perfusion of 2 Jll 20 hours (4 cycles) Regimen C: dose via days .2-quinolone 200-2000 mg / m2 / day i. v. J? -J5 or 5-50 mg / kg / day 1-hour infusion .metotrexate 690 mg / m2 i.v. J1-J 10 continuous infusion of 42 hours .leucovorin 15 mg / m "oral J2-J5 every 6 hours 15 1.1.2 Hoelzer protocol The products may be added to the cytotoxic drugs of the polychemotherapy protocol (D. Hoelzer et al. collaborators, Blood 1984; 64: 38-47, D. Hoelzer et al., Blood 1988; 71: 123-131) according to the following scheme: ii) induction chemotherapy / Phase 1 25 ^^^ dose via days .2-quinolone 200-2000 mg / m2 / day i.v. J1-J5, J - J1: or 5-50 mg / kg / day Ji5 ~ J? « perfusion of 1 h .daunorubicin 25 mg / m "i.v. J?, J8, J? s J2- .vincristine 1.5 mg / m "i.v. J?, J8, Ji5, (maximum 2 mg) J22 .prednisone 60 mg / m "oral J? ~ J28 fifteen . L-aspargmasa 5000 U / pr .m. J?, J? 4 (maximum 2 mg) ii) Induction chemotherapy / Phase 2: The induction phase may be carried out as follows: doses via days 2-quinolone 200-2000 mg / m "/ day i.v. J2 ° -J33, J36- or 5-50 mg / kg / day Jo, J42-J." 1 hour infusion cyclophosphamide 650 mg / m2 i.V. J29f J < i3r Js .citarabine 75 mg / m / day i.v. J3? -J34, perfusion of 1 hour J38-J4 ?, .mercaptopurine 60 mg / m2 oral J29-J57 .metotrexate 10 mg / m "/ day 1. v. J31 / J38. J45 maximum 15 mg) J52 iii) re-induction chemotherapy / Phase 1: -a_- _ _ ^ _- ¿^ * gtósáfe dose via days 2-quinolone 200-2000 mg / m / day i.v. J: -Js, J- ?, or 5-50 mg / kg / day J15-J1-. Infusion of 1 hr J22 ~ J26 .doxorubicin 25 mg / m2 / day i.v. Jl, J8, Jl5 J2 ~ .dexametasone 10 mg / mOral day J1-J2 .vincristine 1.5 mg / m2 / day oral J?, J8, Ji5 (maximum 2 mg) oral and J22 iv) re-induction chemotherapy / Phase 2: dose via days 2-quinolone 200-2000 mg / m2 / day i.v. J31-J35A3- or 5-50 mg / kg / day -J42 perfusion of 1 h cyclophosphamide 650 mg / m2 i.v. J2 (maximum: 100 mg) t &Áat .:. 1.., . ..? Ugly-to-? dose via days .citarabine 75 mg / m2 i.v. Js: -J34, - . Thioguanine 60 mg / m "oral J29-J 1. 2. Acute myeloid leukemia: 1. 2.1.Adult treatment of all ages The 2-quinolones can be added, according to the following scheme, to the treatment that incorporates the standard dose of cytarabine previously described by R.O. Dilleman et al. (Blood, 1991; 78: 2520-2526), Z.A. Arlin et al. (Leukemia 1990; 4: 177-183) and P.H. Wiernik et al. (Blood 1992; 79: 313-319): dose via days , 2-quinolone 200-2000 mg / m2 / day i.v. J1-J1: or 5-50 mg / kg / day 1-hour infusion dose via days . cytarabine 100-200 mg / m2 / day i. v. Jx-J- in continuous perfusion .daunorubicin 45 mg / m2 / day in i.v. J1-J3, bolus (30 mg / m2 / day or J8-J? O if age> 60 years 10 mitoxantrone 12 mg / m "i. v. J1-J3 in daily bolus fifteen . idarubicin 13 mg / m "i.v. J1-J3 in daily bolus 1. 2.2.Treatment of the adult aged less than 60 20 years i) induction chemotherapy: This cycle of induction incorporates the administration of cytarabine in high doses according to the following scheme: feU-t-l-i máeußÉ? my-, 4 jrtfcka-fca .., - dose via days 2-quinolone 200-2000 mg / m2 / day i.v. J? -J? C or 5-50 mg / kg / day 1-hour infusion Ara-C 2000 mg / day i.v. Ji-Je (cytarabine) in 2-hour infusion, every 12 hours . daunorubicin 60 mg / m "/ day i.v. J 4-" JU6 in 24-hour continuous infusion. .citarabine 3000 mg / m "/ day i.v. Ji - J5 in infusion of 1 hour every 12 hours .daunorubicin 45 mg / m "in bolus i.v. J7-JE every 24 hours (in order to reduce the risk of S.N.C. toxicity, in case of renal failure, adjust the cytarabine dosage to the clarity of the cratinin) according to L. E. Damon et al. (Leukemia 1994; 8: 535-541), G.L. Phillips et al., (Blood 1991; 77: 1429-1435) and G. Smith et al. (J. Clin. Oncol. 1997; 15: 833-839). ii) consolidation chemotherapy: The cycle, described below, will be repeated 8 times, at a rate of 1 cycle every 4 to 6 weeks (according to R. J. Mayer et al, N. Engl J. Med. 1994; 331: 896-903): 15 doses per day .2-quinolone 200-2000 mg / m / day i.v. J1-J5 or 5-50 mg / kg / day 20 perfusion of 1 h .citarabine 3000 mg / m2 i.v. J1, J3, in perfusion of 3 J5 hours every 12 hours 25 (4 cycles) then .citarabine 100 mg / m2 / day s.c. J1-J5 .daunorubicin 45 mg / m2 in bolus i.v. Jx (4 cycles) iii) consolidation chemotherapy (with a strong dose of cytarabine): the cycle, described below, should be repeated 2 times and is adapted according to G. L. Phollips et al. (Blood 1991; 77: 1429-1435); S.N. Wolf et al (J. Clin. Oncol., 1989; 7: 1260-1267); R.J. mayer et al. (N. Engl. J. Med. 1994; 331: 896-903): dose via days .2-quinolone 200-2000 mg / m / day i.v. Ji-Jm or 5-50 mg / kg / day 1-hour infusion . cytarabine 3000 mg / m2 i. v. Ji-Je 1 hour every 12 ^^^ s ^^ te ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ hours . daunorubicin 30-45 mg / m / day i. v. J - J-, in bolus, once a day 1. 2.3. Treatment of the adult of 60 years or older The claimed substances may be added to the following consolidation chemotherapy protocols: i) according to R.O. Dilman et al (Blood 1991; 78; 2520-2526), Z.A. Arlin et al. (Leukemia 1990; 4; 177-183), P.H. Wiernilk et al (1992; 79: 313-319): dose via days . 2-quinolone 200-2000 mg / m2 / day i. v. J? ~ J6 or 5-50 mg / kg / day 1-hour infusion i.l. ~ .- **. »,, * - btíaé ... - ^^ ^ - < MaMÉ? ^^ - i --- dose via days .citarabine 100-200 mg / m "i.v. Ji-Js (Ara-C) 24-hour continuous infusion . daunorubicin 30-45 mg / p / day i.v. Jl, J2 in bolus or .mitoxantrone 12 mg / m "/ day i.v. Ji, J2 in bolus or 15 idarubicin 13 mg / m "/ day i.v. Ji, J in bolus ii) according to R.J. Mayer et al (N. Engl. J. Med. 194; 331: 896-903): 20 doses via days 2-quinolone 200-2000 mg / m2 / day i. v. J? -J6 or 5-50 mg / kg / day 25 perfusion of 1 h dose via days .citarabine 100 mg / m2 i.v. J2_Js 24-hour continuous perfusion (4 cycles) then .citarabine 100 mg / m2 s.c. Ji, J5 every 12 hours .daunorubicin 45 mg / m2 / day i.v. Ji in bolus (4 cycles) iii) according to C.A. Linker et al. (Blood 1993; 81: 311-318), N. Chao et al. (Blood 1993); 81: 319-323) and A.M. Yeager et al. (N. Eng. J. Med. 1986; 315: 145-147): This protocol includes an autologous bone marrow transplant (performed on day J0): dose via days 2-quinolone 200-2000 mg / m2 / day i.v. J --- J- or 5-50 mg / kg / day 1-hour infusion busulfan 1 mg / kg in oral qid J-7 to J-4 (to the total of 16 doses) etoposide 60 mg / kg / day i.v. J_- 10-hour infusion dose via days 2-quinolone 200-2000 mg / m / day i.v. J-.9-J-1 or 5-50 mg / kg / day 1-hour infusion usulfan 1 mg / kg in oral qid J_g to J_ dose via days cyclosphosphamide 50 mg / kg / day i.v. J-s to J_2 perfusion of 1 hour iv) in case of HLA-compatible allogeneic bone marrow transplantation according to: P.J. Tutscha et al Blood 1987; 70: 1382-1388, F.R. Applebaum et al., Ann. Int. Med. 1984; 101: 581-588: dose via days .2-qumolone 200-2000 mg / day i.v. J-7-J-1 or 5-50 mg / kg / day 1-hour infusion .busulfan 1 mg / kg in oral qid J-7 to J_ (in total 16 days) cyclophosphamide 60 mg / kg / day i.v. J_3 a J_2 1 hour infusion 2"/ Chronic adult leukemia 2. 1. Chronic myeloid leukemia In the myeloblastic phase, the 2-quinolones can be added to the HU-Mith treatment, described by C.A. Koller et al. (N. Engl. J. Med. 1986; 315: 1433-1438): doses viai days .2-quinolone 200-2000 mg / m2 / day i.v. J1-J5 or 5-50 mg / kg / day J8-J12 perfusion for 1 h J15-J19 15 J22-J25 .hydroxyurea 500 mg / day oral diary .mitramycin 25 μg / kg / day i.v. daily 20 perfusion of 2 a for 3 4 hours weeks then 3 times a week 2.2. Chronic lymphocytic leukemia < ^^^^^ j¡l $ 2 ™ ^ ^^ i ^^ j ¡Q¿¡ ^ 2.2.1. FCG-CLL protocol The 2-quinolones can be added to the "forced chlorambucil" combinations such as those described by E. Kimby et al. (Leuk, Lymohoma 1991; 5 (Suppl.) 93-96) and by the FCGCLL (Blood 1990; 75: 1422-1425): doses via days .2-quinolone 200-2000 mg / m2 / day i. v. J1-J5 or 5-50 mg / kg / day J8-J12 1-hour infusion J15-J22 15 .clorambucil 0.1 mg / kg / day oral 1 time / day or .clorambucil 0.4 mg / kg / day oral Jl 20 and .prednisone 75 mg / day oral J1-J3 2. 2.2. Fludarabine-CdA Protocol 25 Tffl ffriHÍH-go »~ * t rt • ..? Nrtf-tf 1 W -? - --- - - • _ .-. .. --- ^ «a» to * - ^ »according to H.G. Chun et al. (J. Clin. Oncol., 1991; 9: 175-188), MJ Keating et al. (Blood 1989; 74: 19-25 / J. Clin. Oncol. 1991; 9: 44-49) and A. Saven et al (J. Clin. Oncol. 1995; 13: 570-574): dose via days .2-quinolone 200-2000 mg / m2 / day i. v. Ji-Je or 5-50 mg / kg / day (1 time / month 1 hour infusion for 6 to 12 cycles) fludarabine 25-30 mg / m "/ day i.v. J? -J_ perfusion for 30 minutes (every 4 weeks for 6 to 12 cycles) or .cladibrin 0.09 mg / kg / day i.v. J1-J7 in continuous perfusion [1 cycle every 28 to 35 days .TO. ,. . j ^ J-aJuS - »... dose via days for 1 to 9 cycles (median: 4 cycles)] 3"/ Lymphoproliferative diseases 3. 1. Hodgkin's disease The 2-quinolones can be incorporated into polychemotherapy protocols classically for the treatment of Hodgkin's lymphoma: 3. 1.1. AVDB protocol according to G. Bonnadonna and collaborators (Cancer Clin. Triáis 1979; 2: 217-226) and G.P. Canellos et al. (N. Engl. J. Med. 1993; 327: 1478-1484): dose via days .2-quinolone 200-2000 mg / m2 / day i.v. J1-J3, or 5-50 mg / kg / day Ji5 ~ J? 8 perfusion of 1 h dose via days .doxorubicin 25 mg / m2 in bolus i.v. Ji, J2; (TO) .bleomycin (B) 10 U / m2 in bolus i.v. Ji, Ji5 .vinblastine (V) 6 mg / m2 in bolus i.v. Ji, Ji5 .carbazine (D) 375 mg / pr in bolus i.v. Jl r Ji5 The cure consists of 6 to 8 cycles, at a rate of 1 cycle every 28 days. 3. 1.2. MOPP / ABVD protocol according to G. Bonnadonna et al (Ann. Intern Med. 1986; 104: 739-746) and G. P. Canellos et al. (N. Engl. J. Med. 1993; 327: 1478-1484): The MOPP protocol must be alternated with the ABVD protocol (see section 3.1.1.) Every 28 days and the cure consists of 6 cycles: '* ^ ~ ** - * -' MOPP Protocol: dose via days .2-quinolone 200-2000 mg / m / day i.v. J2-J3, or 5-50 mg / kg / day J3-J11 and 1-hour infusion Ji4-Ji7 .methroretamine 6 mg / m2 in bolus i.v. Ji, J8 (M) .vincristine (O) 1.4 mg / m2 in bolus i.v. Jx, J8 (there is no maximum) .procarbazine 100 mg / nr / day oral J1-J14 (P) .prednisone (P) 40 mg / m2 / day oral J1-J14 3. 1.3. Stanford Protocol V according to N. L. Bartlett et al. (J. Clin. Oncol., 1995; 13: 1080-1088): dose via dias .2-quinolone 200-2000 mg / m2 / day i. v. J1- J5, or 5-50 mg / kg / day J8- J12 perfusion of 1 hr Jl5"Jl 9 J22- J26 . doxorubicin 25 mg / m "i.V. Jl, J15 .vinblastine 6 mg / m "in bolus 1. v. Jl, Jl5 (4 mg / m" in the course of cycle 3 if age> 50 years) .meclohetamine 6 mg / m "in bolus i.v. Jx (M) .vincristine 1.4 mg / m2 in bolus i.v. Jlf J25 (max. Dose: 2 mg) [1 mg / m "over the course of cycle 3 if age> 50 years] .bleomycin 5 U / m2 1. v. J8, J22 dose via days .eposited 60 mg / m "i.v. J? 3 io .prednisone 40 mg / m2 / day oral 1 time / week (weeks 1-9) The cure consists of 3 cycles at a rate of 1 cycle every 28 days. 3. 1.4. EVA Protocol according to G.P. Canellos et al (Proc. Am. Soc. Clin. Oncol. 1991; 10: 273): dose via days .2-quinolone 200-2000 mg / m2 / day i.v. J1-J5, or 5-50 mg / kg / day 1-hour infusion .etoposide (E) 100 mg / m2 oral J?, J2, J3 perfusion of 2 L & amp; &'' and dose via days hours vinblastine (V) 6 mg / m "in bolus i.v. Ji .doxorubicin (A) 50 mg / m2 in bolus i.v. Jx The cure consists of 6 cycles, at a rate of 1 cycle every 28 days. 3. 1.5.protocol B-VAVe according to W.G.Harker et al. (Ann.Inter.Med. 1984; 101: 440-446): dose via days . 2-quinolone 200-2000 mg / m2 / day i. v. J1-J3 or 5-50 mg / kg / day 1-hour infusion .bleomycin (B) 5 U / m2 in bolus i.v. J2 .lomucine (CCNU) 100 mg / m2 oral Ji dose via days .doxorubicin (A) 60 mg / m "in bolus i.v. J ^ . vinblastma (Ve) 5 mg / m "in bolus i.v. J: The cure consists of 8 cycles, at a rate of 1 cycle every 28 days. 3. 2. Non-Hodgkin's linfornas 3. 2.1. of low degree of malignancy i) CVP protocol -according to C.M. Bagley et al. (Ann Intern. Med. 1972; 76: 227-234) and C.S. Portlock et al. (Blood 1976; 47: 747-756) dose via days .2-quinolone 200-2000 mg / m2 / day i.v. J1-J5 or 5-50 mg / kg / day perfusion of 1 h dose via days A ^ & dose via dias cyclophosphamide 300-400 mg / m2 / day oral Ji, J5 (C) .vincristine (V) 1.4 mg / m2 in bolus i.v. Ji (max: 2 mg) .prednisone (P) 100 mg / m2 / day oral J1-J5 this cycle is repeated every 21 days until maximum response ii) -I-COPA protocol -according to RV Smalley et al. (N. Eng. J. Med. 1992; 327: 1336-1341) dose via days .2-quinolone 200-2000 mg / m2 / day i. v. J1-J5 or 5-50 mg / kg / day perfusion of 1 h dose via days cyclosphosphamide 600 mg / m2 in bolus i.v. J: .vincristine (0) 1.2 mg / m2 in bolus i.v. Jx (C) (max: 2 mg) .prednisone (P) 100 mg / m2 / day i.v. J1-J5 .doxorubicin (A) 50 mg / m2 in bolus i.v. Ji . interferon-alpha 6 MU / m2 i.m. J22-J26 (I) the cure comprises 8 to 10 cycles, at a rate of one cycle every 28 days. iii) - fludarabine-CdA protocol -according to P. Solol-Celigny et al. (Blood 1994; 84 (Supp.1): 383a), H. Hoeschster et al .; (Blood 1994; 84 (Suppl.1): 564a and A.C. Kay (J. Clin. Oncol. 1992; 10: 371-377) dose via days , 2-quinolone 200-2000 mg / m2 / day i.v. J.-J- or 5-50 mg / kg / day 1-hour infusion fludarabine 25 mg / m2 / day i.v. J1-J5 perfusion of o.5 hours .fludarabine 20 mg / m / day i.v. J1-J5 and cyclophosphamide 600-1000 mg / m "/ day i.v. or cladribine 0.1 mg / pT / day i.v. J1-J7 24-hour infusion For fludarabine, each cycle is repeated every 28 days; for the cladpbina, each cycle is repeated every 35 days. 3. 2.2. of degree of intermediate malignancy i) -CHOP or CNOP protocol -according to EM McKelvey et al (Cancer 1976; 38: 1484-1493), J.O. Ar itage et al. (J. Clin. Oncol. 1984; 2: 898-902), S.Paulovsky et al. (Ann. Oncol. 1992; 3: 205-209) dose via days 2-quinolone 200-2000 mg / m ~ / day i.v. J1-J5 or 5-50 mg / kg / day 1-hour infusion cyclophosphamide 750 mg / m "/ day i.v. Jx (C) .doxorubicin (H) 50 mg / m 'in bolus i.v. Jx .vincristine (O) 1.4 mg / m2 in bolus i.v. Jx (max: 2 mg) .prednisone (P) 100 mg / m2 / day oral J1-J5 (in 1 dose / day) for the CHOP protocol l. ty-.s? -? - -.

Mitoxantrone (N) can be used to replace (CNOP protocol) doxorubicin in patients over 60 years (dose: 12 mg / m2 in bolus i.v. to day Jl of each cycle).

Healing by the CHOP or CNOP protocol includes 6 to 8 cycles at a rate of 1 cycle every 21 days. ii) MACOP-B protocol according to P. Klimo et al. (Ann.Inter.Med. 1985; 102: 596-602) and I.A. Cooper et al. (J. Clin. Oncol., 1994; 12: 769-778) dose via days .2-quinolone 200-2000 mg / m2 / day i.v. J1-J5A8-J12, or 5-50 mg / kg / day J15-J22 / J29- 1-hour infusion J33A43-J47, .metotrexate (M) 100 g / rn ^ in bolus i. v. JsA3dA6 then 300 mg / m2 perfusion of 4 doses per week. Leucovorin 15 mg in oral qid Jg, J37, J65 .doxorubicin (A) 50 mg / m "in bolus i.v. J?, Ji5f -.9 Cyclophosphamide 350 mg / m2 in bolus i.v. JI, JSA2Q .vincristine (O) 1.4 mg / m2 in bolus i.v. J8 / J22. J36 (max .: 2 mg) J50 J64 J78 .prednisone (P) 75 mg / day oral daily, for 12 weeks .bleomycin (B) 10 U / m "in bolus i.v. J22A50 / J78 This treatment protocol extends in 2 weeks and corresponds to 1 cycle. iii) -Protocol VACOP-B according to J.M. Connors et al. (Proc. Am. Soc. Clin. Oncol. 1990; 9: 254): dose via days , 2-quinolone 200-2000 mg / m2 / day i.v. J1-J5A3-J1, or 5-50 mg / kg / day J15- J22. J29- 1-hour infusion J34 / J43- J , etoposide (V) 50 mg / m "1. V. Jib / J43.J 71 .postoposide 100 mg / m "oral Ji6, Ji7 J44í doxorubic (A) 50 mg / m "in bolus i.v. J?, J? sA29, Cyclophosphamide 350 mg / m2 / day in i.v. J8, J22 / J36 [c) bolus J5oAe4 J78 .vincristine (O) 1.2 mg / m "in bolus i.v. J8, J22A36, J50.J4, Jie dose via days .prednisone (P) 45 mg / m2 / day oral 1 / day for 1 week, then 4 / day for 11 weeks.

Each cycle for 12 weeks iv) -protocol m-BACOD / M-BACOD -according to M.A. Shipp et al. (Ann. Int. 15 Med. 1986; 140: 757-765) and A.T. Skarin et al. (J. Clin. Oncol. 1983; 1: 91-98) dose via days 2-quinolone 200-2000 mg / m2 / day i.v. J-J5, or 5-50 mg / kg / day J8-J12 perfusion of 1 J15A9 hour dose via days .metotrexate 200 mg / m2 i.v. J 8ß l, J "- 15 (m) 4 hour infusion or o (M) 3000 mg / m2 i.v. J perfusion of 4 hours .leucovorin 10 mg / m2 in oral qid Jg, Jiß (6 doses in total or Jie .bleomycin (B) 4 U / rrr in bolus i.v. Ji .doxorubicin (A) 45 mg / m2 in bolus i.v. Ji cyclosphosphamide 600 mg / m2 in bolus i.v. Ji (C) .vincristine (0) 1 mg / m2 in bolus i.v. Ji .dexametasone (D) 6 mg / m2 / day oral J3-J5 The cure consists of 10 cycles, at a rate of 1 cycle every 21 days. v) -Protocol ProMACE / CytaBOM -according to D. L. Longo et al (J. Clin. Oncol., 1991; 9: 25-38): dose via days .2-quinolone 200-2000 mg / m2 / day i.v. J-J5, 1-hour infusion cyclosphosphamide 650 mg / m "i.v. Ji (C) 0.5 hour infusion .doxorubicin (A) 25 mg / m2 in bolus i.v. Ji .eposited 120 mg / m2 i.v. Ji perfusion of 1 hour dose via days .prednisone (P) 60 mg / day oral Jx-J? - .citarabine 300 mg / m "in bolus i.v. J8 .bleomycin (B) 5 U / m "in bolus i.v. Js .vincristine (0) 1.4 mg / m2 in bolus i.v. J8 .metotrexate 120 mg / m2 in bolus i.v. J8 , leucovorin 25 mg / m2 in oral tid Jg (4 doses in total) Healing consists of 6 to 8 cycles, at a rate of 1 cycle every 14 days. 3. 2.3. of low or intermediate degree of malignancy i) - ESHAP rescue protocol -in case of recidivism or in case of failure of the first line treatment, according to W.S. Velásquez et al. (J. Clin. Oncol. 1994; 12: 1169-1176) dose via days , 2-quinolone 200-2000 mg / m2 / day i.v. Jx-J ?, or 5-50 mg / kg / day 1-hour infusion etoposide (E¡ 40 mg / m2 i.v. J? ~ J4 2-hour infusion .metilprednisol- 500 mg / day Ji, J canvas (S) perfusion 15 minutes cirarabine (HA) 2000 mg / m2 i.v. J5 perfusion of 3 hours .cisplatin (P) 25 mg / m "/ day in i.v. J? ~ J bolus, 24-hour continuous infusion ./-S - Healing consists of 6 cycles, at a rate of 1 cycle every 28 days. ii) - MINE rescue protocol -in case of recidivism or in case of failure of the first line treatment, according to F. Cabanillas et al. (Semin Oncol 1990, 17 (Suppl 10), 28-33) dose via days 2-quinolone 200-2000 mg / m2 / day i.v. JX-JE or 5-50 mg / kg / day 1-hour infusion Ifosfamide (I) 1330 mg / m "i. V. J1-J3 1-hour infusion .mesna (M) 1330 mg / m "i.v. J1-J3 in the perfusion of ifosfamide then 266 mg / m2 in bolus 4 and 8 hours after dose via days of each dose of ifosfamide mitoxantrone (M) 8 mg / m2 i.v. Ji perfusion of 15 minutes . etoposide (E) 65 mg / m "/ day i.v. J1-J3 perfusion 1 hour This cycle is repeated every 21 days. 3. 3. Non-Hodgkin's lymphoma: Burkitt's lymphoma, small cell lymphoma, lymphoblastic lymphoma .. 3. 3.1.Magrath protocol -The claimed products may be associated with the Magrath protocols according to the following schemes: i) -cycle 1 -according to I.T. Magrath et al. (Blood 1984; 63: 1102-111) dose via days 2 - . 2-quinolone 200-2000 mg / m2 / day i.v. J -Js perfusion of 1 hour .citarabine 30 mg / m2 intra-Ji, J:, spinal J3, J7 . cyclophosphamide 1200 mg / m "in 1. v. bolus .metotrexate 12.5 mg / m2 intra-Jio (max: 12.5 mg) spinal methotrexate 300 mg / m "/ day 1. v. Jio- J11 perfusion of 1 hour, then 60 mg / m" / h perfusion of 41 hours dose via days .leucovorin 15 mg / m "in bolus i.v. For co-enzyme (8 doses after sivas) of the principle of methotrexate administration ii) -cycles 2 to 15 -according to I.T. Magrath et al. (1984) also dose via days .2-quinolone 200-2000 mg / m2 / day i.v. Jx-J or 5-50 mg / kg / day J infusion of 1 J .X hour .citarabine 45 mg / m "intra-J1A2 spinal (cycles 2 and 3) dose via days Jl (cycles 4 and 6) cyclophosphamide 1200 mg / m "in í.v. Ji bolus doxorubicin 40 mg / m "in i .. v. Ji bolus .vincristine 1.4 mg / m "in i.v. bolus (max: e mg) 15 .metotrexate 12.5 mg / m inbra- J2f JlO (max: 12.5 mg) marrow (cycles 2 and 3) Jio (cycles 4,5,6) .metotrexate 300 mg / m "i. v. JlO / Jll perfusion of 1 (cycles hour, then 60 i and 6) dose via days mg / m2, perfusion JiíAis continuous of 41 (cycles hours 7-15) leucovorin 15 mg / m "in bolus i.v. Start qid (8 doses in the 42 secutivas ava treatment time by meto trexate The cure consists of 14 cycles, at a rate of one cycle every 28 days. 3. 4. Aldenstrom macroglobulinemia 3. 4.1. CVP protocol -according to the CVP protocol described by M.A. Dimopoulous et al. (Blood 1994; 83: 1452-1459) and C.S. Portlock et al. (Blood 1976; 47: 747-756): dose vii days .2-quinolone 200-2000 mg / m2 / day i.v. J? -J_. or 5-50 mg / kg / day 1-hour infusion Cyclophosphamide 300-400 mg / m2 / day oral J1-J5 (C) .vincristine (V) 1.4 mg / m2 / day i.v. Ji .prednisone (P) 100 mg / m2 / day oral J1-J5 the healing is to continue indefinitely (1 cycle every 21 days). 3. 4.2. Fludarabine-CdA Protocol according to H.M. Kantarjan and collaborators (Blood 1990; 75: 1928-1931) and M.A. Dinopoulous et al. (Ann. Intern. Med. 1993; 118: 195-198): dose via days 2-quinolone 200-2000 mg / m2 / day i.v. JX-JE or 5-50 mg / kg / day 1-hour infusion fludarabine 25-30 mg / m2 i. v. Ji-Js perfusion of 0.5 hours or dose via days .2 -quinolone 200-2000 mg / m2 / day i.v. J-Jv or 5-50 mg / kg / day 1-hour infusion , cladribine 0. 09 mg / m2 / day i. v. J1-J7 ¡CdA) continuous perfusion healing consists of 6 to 12 cycles spaced out in 28 days in the case of fludarabine and 2 cycles spaced in 28 days equally in the case of cladribine. and ^^^^^^^^^^ J 3.5. Multiple myeloma 3. 5.1.MP protocol according to R. Alexanian et al (JAMA 1969; 208: 1680-1685), A. Belch et al. (Br. J. Cancer 1988; 57: 94-99) and F. Mandelli et al. (N. Engl. Med. 1990; 322: 1430-1434): dose via days .2-quinolone 200-2000 mg / m2 / day i.v. J -JE or 5-50 mg / kg / day 1-hour infusion .melfalan (M) 0.25 mg / kg / day oral J? ~ J .prednisone (P) 100 mg / day oral J? ~ J4 ^^ MÉM ^ M ^ MMÍÍMMM ^ ^ MÍM¿ ^ MIMM ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ * ^ »§« & ^ - < & * YES. »Or dose via days .2-quinolone 200-2000 mg / m2 / day i.v. J? ~ S or 5-50 mg / kg / day 1 hour infusion .melfalan (M) 9 mg / kg / day oral J? ~ J4 .prednisone (P) 100 mg / day oral J? ~ J4 the cure consists of at least 12 cycles, at the rate of 1 cycle every 4 to 6 weeks. 3. 5.2. VAD protocol according to B. Barlogie et al. (N. Engl. J. Med. 1984; 310: 1353-1356): dose via days .2-quinolone 200-2000 mg / m2 / day i.v. J? - 5 or 5-50 mg / kg / day 1 hour infusion .vincristine (V) 0.4 mg / day i.v. J? ~ J4 24-hour continuous infusion .doxorubicin (A) 9 mg / m2 / day i.v. J? ~ J 24-hour continuous infusion .dexametasone (D) 40 mg / day i.v. JI ~ J? 3. 5.3.Protocol MP-mterferon a according to O. Osterborg et al. (Blood 1993; 428-1434): dose via days .2-quinolone 200-2000 mg / m2 / day i.v. J-J5 or 5-50 mg / kg / day 1-hour infusion .melfalan (M) 0 .25 mg / kg / day oral J? ~ J4 . prednisone (P) 2 mg / kg / day oral J? -J4 . interf eron-alf at 7 MU / m2 / day s. c. J1-J5 and J22-J26 The cure consists of the indefinite repetition of this cycle, at the rate of 1 cycle every 42 days. 3. 5.4. VCAP or VBAP protocol according to S.E. Salmon et al. (J. Clin.

Oncol. 1983; 1: 453-461): VCAP protocol: dose via days .2-quinolone 200-2000 mg / m2 / day i.v. J? -JE or 5-50 mg / kg / day 1 hour infusion .vincristine (V) 1 mg / m2 in bolus i.v. Ji (max: 1.5 mg) .doxorubicin (A) 30 mg / m "in bolus i.v. Ji .prednisone (P) 60 mg / m "/ day oral J? ~ J cyclophosphamide 125 mg / m "oral J? _J4 (C) 1 hour infusion VBAP protocol: cyclophosphamide is replaced by rmustine (BCNU), the rest is identical dose via days .carmustine 30 mg / m "i.v. Ji infusion of 1 hour C. NINO'S TUMORS-Pediatric Oncology Isoflavones can also be incorporated into poly-chemotherapeutic protocols for the treatment of pediatric tumors in order to improve antitumor efficiency by totally reducing the severity of side effects thanks to the action on the recruitment and mobilization of clonogenic cells and the possibility of reducing the active doses. l ° / Sarcoma d'Ewing / Primitive neuroectodermal tumor 2-quinolones can be introduced into the VCR-Doxo-CY-Ifos-Mesha-E protocol (ED Berger et al, J. Clin Oncol 1990; 8: 1514-1524; WH Meyer et al. J. Clin. Oncol. 1992; 10: 1737-1742): dose via days .2-quinolone 100-200 mg / m2 / day i.v. Jx-J5 or 2-50 mg / kg / day and J22-J2V perfusion of 1 and J43-J48 and J63-J68 dose via days vmcristin 2 mg / m2 in bolus 1 -V. Ji / s / (maximum dose = 2 JX5 / J43 mg) doxorubicin 30 mg / m2 / day i.v. J? -J, in perfusion of 24 J43"J 5 hours cyclophosphamide 2.2 g / m "i.v. l, J. 43 in perfusion 0.5 hours ifosfamide 1800 mg / m2 / day i.v. J22- J26 in perfusion of 1 Jß3- Jd7 hour mesna 360 mg / m "1. v, administer perfusion of 15 brought with minutes at the rate of cyclophos5 dose every 3 hofamide e ras ifosfamida dose via days .eposited 100 mg / m2 i.v. J2-J2L- in perfusion of 1 is-Jß- hour The cure includes 6 to 10 of these cycles depending on the initial severity of the sarcoma and the amplitude of the response. 2"/ Child's acute lymphoblastic leukemia 2. 1. Induction chemotherapy (days J? ~ J-3o) The 2-quinolones can be added to the recommended protocols (PS Gaynon et al., J. Clin. Oncol., 1993, 11, 2234-2242; J. Pullen et al., J. Clin. Oncol., 1993; 11: 2234-2242; J. Pullen et al., J. Clin. Oncol., 1993; 11: 839-849; VJ Land et al., J. Clin. Oncol., 1994; 12: 1939-1945): dose via days 2 - . 2-quinolone 100-200 mg / m2 / day i .v. JX-J? or 2-50 mg / kg / day and Jß-J ?? perfusion of 1 and? 5-J? « vincristine 1.5 mg / m2 in bolus i.v. JiAsAis (maximum dose = 2 mg) J22 , L-asparginase 6000 IU / m2 i.m. 3 times / week du dose via days 3 weeks .prednisone 60 mg / m "oral Ji to J 28 in 3 doses / day .daunorubicin 25 mg / m2 / day i.v. J?, Js. J15 in perfusion of 15 and J22 minutes .metotrexate function of intra-J15 age, J2e dose via days spinal .citarabine function of intra-J age: spinal depending on the result of the bone marrow examination, the transition to the consolidation phase is made on day J28 of the treatment protocol. 2. 2. Consolidation / maintenance chemotherapy The 2-quinolones can be introduced into the maintenance protocol (P. S. Gaynon et al. J. Clin.

Oncol. 1993; 11: 2234-2242; J. Pullen et al., J.

Clin. Oncol. 1993; 11: 839-849; V.J. Land and collaborators, J. Clin. Oncol. 1994; 12: 1939-1945) according to the following scheme: ._. " .2-quinolone 100-200 mg / m2 / day i.v. Jx-J5 JX? - or 2-50 mg / kg / day J20 and JS4- perfusion of 1 J99. J? Ox- hour J106, J or ß dose via days -J, A, cyclophosphamide 1000 mg / m2 i.v. J?, J? S, in perfusion of 0.5 J122 hours L-asparginase 6000 U / m2 i.v. 3 times / week cytarabine 75 mg / m "/ day i.v. a sequence in infusion of / s, of 4 15 minutes days starting J2 doxorubin 25 mg / m "/ day i.v. Jg4A? oi / in perfusion of 15 J? 08 minutes dose via days .mercaptopurine 60 mg / m2 / day oral Ji / J ° 3. Ji-s at the end of treatment .metotrexate 20 mg / m2 / day oral 1 time / week between J35 between J143 and the end of the treatment .prednisone 40 mg / m "/ oral day 5 days with¬ (divided into 3 consecutive / dose / day) month between the end of treatment twenty . Thioguanine 60 mg / m2 / day oral Ji22- J135 .vincristine 1.5 mg / m2 in bolus i.v. Jg4, J? Oi (maximum dose = 2 mg) Jioß des¬ times 1 time / - - > .t? ^ Wtnnmw - * '^ * fo fe £ fr Qlt &itííkMfr & * - • * • - - dose via days month between the end of the treatment .metotrexate in function of the intra- J?, Js, Ji5 aged rachi- J22. J123, deo J130 then 1 time / 3 months between the end of the treatment 3 ° / acute myeloid leukemia of the child The 2-qu? Nolones are added to the induction and consolidation / maintenance protocols according to the following schemes: 3. 1. Induction chemotherapy according to Y. Ravindranath et al. J. Clin. Oncol. 1991; 9: 572-580; M. E. Nesbit et al. J. Clin. Oncol, 1994; 12: 127-135; RJ Wells et al., J. Clin. Oncol. 1994; 12: 2367-2377): dose via days .2-quinolone 100-200 mg / m2 / day. ? G. J-J5, or 2-50 mg / kg / day JX O _ JX 3 1-hour infusion cytarabine according to the intrarachidian age .daunorubicin 20 mg / m2 / day i.v. Jx-J4, in perfusion of JXO ~ JX3 24 hours cytarabine 200 mg / m2 / day i.v. J-J4, in perfusion of JXO ~ JX2 24 hours dose via days .thioguanine 100 mg / m2 / day oral Jx-J divided into 2 Jio'Ji: dose per day .eposited 100 mg / m2 / day i .v. dose via days in perfusion of -J-L. .dexametasone 6 mg / m2 i.v. Jx-J4, divided into 3 / oral? Or ~ Jx dose / day this cycle repeats from J28- 3. 2. Consolidation / maintenance chemotherapy according to Y. Ravindranath et al J. Clin. Oncol. 1991; 9: 572-580; ME. Nesbit et al., J. Clin. Oncol. 1994; 12: 127-135; R. J. Wells et al., J. Clin. Oncol. 1994; 12: 2367-2377): dose via days cytarabine according to intra-Jx age, J2ß / raqui- Js6 dea 2-quinolone 100-200 mg / m2 / day i.v. J -J5, Jß- or 2-50 mg / kg / day J13.J28-J-3 doses via days perfusion of 1 Jse'Jßx 'Jes cytarabine 3000 mg / m2 i.v. Jx-J2, and J8 in perfusion of 3 -Js hours every 12 hours L-asparginase 6000 IU / m2 i.m. J2, J9 3 hours after cytarabine vincnstina 1.5 mg / m2 in bolus i.v. J2ß, J56 (maximum dose = 2mg) Thioguanine 75 mg / m2 / day oral J 2, n8-J "84 doses via days cytarabine 75 mg / m2 / day i .v. , -J, in bolus cyclophosphamide 75 mg / m2 / day i.v. J2ß-J3 in 0.5 hour infusion dose via days cytarabine 25 mg / m2 / day s.c. Jß9-J93 in bolus / i.v.

Thioguanine 50 mg / m2 / day oral Jß9_J etoposide 100 mg / m2 / day i. v. 8g í «- > 92 in 1 hour infusion dexamethasone 2 mg / m2 / day oral Ja9-92 daunorubicin 30 mg / m2 i .v. Jf in 15 minute infusion 4"/ Child's Hodgkin's disease The 2-quinolones can be added to the MOPP-ABVD protocol according to EA Gehan et al. (Cancer 1990; 65: 1429-1437), SP Hunger et al. (J. Clin. Oncol. 1994; 12: 2160-2166) and MM Hudson et al. collaborators (J. Clin. Oncol., 1993; 11: 100- 108): doses via days .2-quinolone 100-200 mg / m2 / day i.v. Jx-J5, or 2-50 mg / kg / day J8-J 2 perfusion of 1 15 hour .methraretamine (M) 6 mg / m2 in bolus i.v. J? / J? .vincristine (0) 1.5 mg / m2 in bolus i.v. J, J8 20 (maximum 2 mg) .procarbazine 100 mg / m2 / day oral J -Ja (P) ^^^^ dose via days .prednisone (P) 40 mg / m2 / day oral JX-J 4 (divided into 3 doses / day) .doxorubicin (A) 25 mg / m2 / day i .v. J29, J_43 in 15 minute infusion .bleomycin (B) 10 U / m2 i.v. J29, J43 in 15-day perfusion .vinblastine (V) 6 mg / m2 in bolus i. v. J29, J < (maximum 2 mg) .carbazine (D) 375 mg / m2 i.v. J2 299, 'Ju.43 in 15 minute infusion This cycle must be repeated 6 times at the rate of 1 cycle every 8 weeks, the cure consists of 6 cycles.

If an autologous bone marrow transplant (autograft) is prescribed, the CVB protocol described by R. Chopra et al. (Blood 1993; 81: 1137-1145), C. Wheeler et al. (J. Clin. Oncol. 1990; 8: 648-656) and RJ Jones et al (J. Clin. Oncol. 1990, 8, 527-537) may be applied according to the following scheme (the allograft has dose via days , 2-quinolone 100-200 mg / m2 / day i .v. or 2-50 mg / kg / day 1-hour infusion cyclophosphamide 1800 mg / m2 / day i. . J_7, J_6 in 2 infusions J_5, _4 of 1 hour carmusina (BCNU) 112 mg / m2 / day i.v. J_7, J_ß in perfusion of 0.5, J. hours dose via days .postposited 500 mg / m2 / day i.v. J_V, J_6 in 2 perfusions -S -4 of 1 hour ° / Lymphoblastic lymphoma of the child The claimed compounds may also be associated with the induction chemotherapy protocols (AT Meadows et al., J. Clin. Oncol., 1989; 7: 92-99- C. Patte et al., Med. Ped. Oncol., 1992; 20: 105. -113 and A. Reiter et al., J. Clin .. Oncol. 1995; 13: 359-372) and maintenance chemotherapy. . 1. Induction chemotherapy dose via days .2-quinolone 100-200 mg / m2 / day i. v. Jx-Js, or 2-50 mg / kg / day x7-J22f perfusion of 1 J24-J29 hour dose per day cyclophosphamide 1200 mg / m2 i.v. J: in 0.5 hour infusion cytarabine according to the intra-Ji rachidian age vincristine 1.5 mg / m2 in bolus i.v. J3, Jio (maximum 2 mg) J17A4 prednisone 60 mg / m "/ day oral J - Jzß divided into 3 doses / day daunorubicin 60 mq / tX i.v. Chi7 in 15 minute infusion L-asparginase 6000 U / m / day i.m. J17-J35 in perfusion of 3 times / 15 minutes week dose via days .metotrexate according to intra-J1- / J-3 age: spinal . 2. Maintenance chemotherapy: according to the following scheme: dose via days 2-quinolone 100-200 mg / trr / day i.v. J-J ?, or 2-50 mg / kg / day J? 5"? Or 'perfusion of 1 J29-J34 hour cyclophosphamide 1000 mg / m "i.v. Ji in 0.5 hour infusion .vincristine 1.5 mg / m2 in bolus oraLl J?, Js (maximum 2 mg) (from cycles 2 to 10) dose vci days methotrexate 300 mg / m2 / day i.v. J 13 (60% in perfusion of 15 minutes and 40% in infusion of 4 hours) leucovorin 10 mg / m / each 4 oral J 16 hours daunorubicin 30 mg / m "i.v. J2g in 0.5 hour infusion methotrexate according to intra-J-, J8, Ji5 rachy- (cycle 1) age, then 1 time / month (cycles 2 to 10) a cure consists of 10 cycles ° / Pediatric Neuroblastoma The polychemotherapy protocol recommended Doxxo-E-Cy-Pt was adapted from R.P. Castleberry et al. (J. Clin. Oncol., 1992; 10: 1299-1304), a. Garaventa et al. (J. Clin. Oncol., 1993; 11: 1770-1779) and D.C. West et al (J. Clin. Oncol. 1992; 11: 84-90): dose via days 2-quinolone 100-200 mg / m2 / day i.v. JX-JE or 2-50 mg / kg / day J28"J35 / perfusion of 1 sß ~ Jes hour .doxorubicin 25 mg / m / day i.v. J2, J30 Js8 in 15 minute infusion .postoposide 100 mg / m "oral / J2.J> J30 in perfusion of naso- J33 JsSf Jßl 1 gastric hour cyclophosphamide 1000 mg / m "i.v, J3, J4, J lr in perfusion of J32f Jd9r JdO 0.5 hours dose via days . cisplatin 60 mg / m "i. v. J?, J2e / Js6 in 6-hour infusion The evaluation of the therapeutic response is made after 9 weeks in order to decide the action to be taken: surgical removal, radiotherapy or new chemotherapy. 7"/ Pediatric Osteosarcoma The 2-quinolones can be added to the Doxo-Pt-Mtx-Lcv protocol as described in M. Hudson et al. (J. Clin. Oncol., 1990; 8: 1988-1997), P.A. Meyers (J. Clin.

Oncol. 1992; 10: 5 - 15), and V.H.C. Bramwell et al.

(J. Clin. Oncol. 1992; 10: 1579-1591): day dose days .2-quinolone 100-200 mg / m2 / day i. . JX-J 'Ss ,, or 2-50 mg / kg / day J' 221X "" 266 'perfusion of J28-J33 hour dose via days . doxorubicin 25 mg / m / day i. v. J ?, J3 in 24-hour infusion . cisplatin 120 mg / m2 i.v. Jx in perfusion of 6 hours .metotrexate 12 mg / m "/ day i.v. J2?, J2- in infusion of 1 hour . leucovorin 100 mg / m "oral J22.J29 every 6 hours 8 ° / Rhabdomyosarcoma of the child The Vcr-Dact-CY-Mesna protocol (H. Maurer et al., Cancer 1993; 71: 1904-1922 and LR Mandell et al., Oncology 1993; 7: 71-83) may include perfusion i.v. of the claimed compounds according to the following scheme: dose via days 2 - . 2-quinolone 100-200 mg / m2 / day i .v. J? -J5, perfusion of 1 J22 ~ J27 .vincristine 1.5 mg / m in bolus i.v. X, J8, J15 (max 2 mg) 22'J29'J38 . Dactinomycin 0.015 mg / kg in i.v. JX-J ?, J22- bolus (daily dose 2- 'J43-47 max: 0.5 mg) 15 cyclophosphamide 2.2 g / m' Jll J '2222 // J "43 .mesna 360 mg / m2 J1'J22'J < in infusion of 1 20 hours every 3 hours for 5 doses At the end of the ninth week of treatment, the efficiency must be evaluated to decide the continuation 25 (surgery, radiotherapy, continue chemotherapy). jfatt? * t ?? MM) tA? t? z »e» i 9"/ Wilms' tumor in the child In the Vcr-Dact protocol as described in GJ D'angio et al. (Cancer, 1989; 64: 349-360) and DM Green et al. (J. Clin. Oncol. 1993; 11: 91-95): dose via days 2-quinolone 100-200 mg / m2 / day i.v. Jx-Js or 2-50 mg / kg / day J8_lTX2 > perfusion of 1 then, every hour week .vincristine 2 mg / m2 in bolus i.v. J7, then (max. Dose: 2 mg) every week . dactinomycin 0. 045 mg / kg in i.v. J, then bolus (P < 30 kg) every 3 1. 35 mg / m2 (P> 30 weeks kg) (maximum dose: 3 mg) This protocol is started after surgical removal.

In the case of autologous bone marrow transplantation (autograft) according to A. Garaventar et al. (Med. Pediatr Oncol 1994, 22: 11-14), the E-Thio-Cy protocol can be modified as follows: 5 doses via days .2-quinolone 100-200 mg / m2 / day i.v. J_8-J_ ?, or 2-50 mg / kg / day 10 perfusion of 1 hour dose víci days .etoposide 1800 mg / m "i.v. J_8 (24-hour infusion) . Thiotepa 300 mg / m ~ / day i.v. J_7, J_6, J_5 20 in 2 hour infusion Cyclophosphamide 50 mg / kg / day i.v. J_, J_3 in perfusion of 1 J-2. J-i 25 hour ^ a, afaaa - tti ---- a - ^ == ----? ^ ¿m¿. ¡___.-. -. * zy * - ^ .- - ~ -, - «t.dataat», the bone marrow transplant takes place on the day Je. statement that does not include process .. >

Claims (22)

1. Use of a compound selected from the compounds of the formula: which is characterized because: X is selected from = 0, = S and = N-NH-R ', R is a phenyl or pyridyl group, R1, R2, RJ and R ", are independently selected from each other among H, OH, an alkyl group in C? -C4 / an alkoxy group in C? ~ C4 a group -OCO-R8, R8 is an alkyl group in C? -C4, and a group derived from a soda, at least one of the substituents R1, R2, R3 , or R4 being different from H, and R2 and R3 can together form a methylenedioxy group. R5 is a phenyl group or a 1 to 3 phenyl group substituted by groups selected from H, OH, a C1-C4 alkoxy group, a -OCOR6 group, a phenyl group (C1-C4 alkoxy), a group -O- SO2-R'8, R 'is a C1-C4 alkyl group or a CFJ group, and a group derived from a osa. R6 is selected from H, an alkyl group in Ci-C, a group -CO-R9 and a group -A-R10, Rda is selected from an alkyl group in C1-C4, a group -CO-R9 and a group -A-R10, R9 is an alkyl group in C? A is an alkylene group in C? -C4. R10 is selected from 5- or 6-membered heterocyclic groups having 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, the CN group, a group -COOR11, -CONR12R13, a group -NR14R15, and a group- COR10, R11, R12, R13, R14, R15 and R16 are independently selected from a hydrogen atom, an alkyl group at C? -C4 and a phenyl group (alkyl at CL-C), R4 and R6 which can also together form a group -CO-CH2-CH2-, for the manufacture of a medicament intended to interfere with the generation of clonogenic cells in tumors during the treatment of these tumors by at least one agent cytotoxic

2. Use according to claim 1, in which the compound is a compound of formula (I) which is characterized in that: -R1 is an alkoxy group in C? ~ C4 -R2 is a hydrogen atom -RJ is an alkoxy group at C2-C4 -R4 is a hydrogen atom,

3. Use according to claim 2, according to which the compound is a clonogenic compound of formula (I) which is characterized in that: -RD is a 4- (alkoxy in C? ~ C4) phenyl group.

4. Use according to claim 3, characterized in that: -R1, is a methoxy group, -R3 is a methoxy group, and -R5 is a 4-methoxyphenyl group.

5. Use according to claim 4, characterized in that the compound is 5,7-dimethoxy-3- (4-methoxyphenyl) -1,2-dihydro-2-quinoline ketone.

6. Use according to claim 4 which is characterized in that the compound is 3- [5, 7-dimethoxy-3- (4-methoxyphenyl) -2-oxo-l, 2-dihydro-l-quinolyl] propanenitrile.

7. Use according to claim 4, characterized in that the compound is l- [2- (1H-1,2,3,4-tetrazol-5-yl) ethyl] -5,7-dimethoxy-3- (4-methoxyphenyl) ) -1, 2-dihydro-2-quinoline ketone.

8. Use according to claim 4, characterized in that the compound is N, N-diethyl-3- [5,7-dimethoxy-3- (4-methoxyphenyl) -2-oxo-l, 2-dihydro-l-quinolyl] -propanamide.

9. A pharmaceutical composition which is characterized in that it has an activity on the pro-formation of clonogenic cells in tumors and which comprises an effective amount of a compound selected from the compounds of the formula: in which: X is selected from = 0, = S and = N-NH-R7, R7 is a phenyl or pyridyl group, R1, R2, R3 and R4 are independently selected from H, OH, an alkyl group at C? ~ C4, an alkoxy group in C? -C4, a group -OCO-R8, RB is an alkyl group in C? -C4 and a group derived from a soda, at least one of the substituents R1, R2, R3, or R4 which are different from H, and R2 and R3 which together can form a methylenedioxy group. RD is a phenyl group or a phenyl group 1 to 3 $ t i. ^ jkta xiy substituted by groups selected from H, OH, an alkoxy group in C? -C4, a group -OCOR8, a phenyl group (C1-C4 alkoxy), a group -0-SO? -R'8, R '8 is an alkyl group in C? -C4 or a group CF3, and a group derived from a soda. R6 is selected from H, an alkyl group in C1-C4, a group -CO-R9 and a group -A-R10, R6a is selected from a group -CO-Rc 'and a group -A-R10, R9 is an alkyl group at C? ~ C, A is an alkylene group in C? -C4. R ± 0 is selected from 5- or 6-membered heterocyclic groups having 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, the CN group, a group -COOR11, -CONR12R13, a group -NR14R15, and a group - COR16, R11, R12, R13, R14, R15 and R16 are independently selected from a hydrogen atom, an alkyl group at C? -C4 and a phenyl group (alkyl at C-C4), R4 and Rd which can also together form a group -CO-CH-CH--. w ^ - ^^^ £ ÉÍifo ^ ¡^ * fc ^

10. Composition according to claim 9, characterized in that the compound is a compound of formula (I) in which: -R1 is an alkoxy group in C? ~ C4 -R "is a hydrogen atom -RJ is an alkoxy group in C? -C -R4 is a hydrogen atom.

11. Composition according to claim 10, characterized in that the compound is a compound of formula (I) in which: R 5 is a group 4- (C 1 -C 4 alkoxy) phenyl.

12. Composition according to claim 11, characterized in that the compound is a compound of formula (I), R1 is a methoxy group, R3 is a? Methoxy group and R5 is a 4-methoxyphenyl group.

13. Composition according to claim 12 which is characterized in that the compound is 5,7-dimethoxy-3- (4-methoxyphenyl) -1,2-dihydro-2-quinolinone.

14. Composition according to claim 12, characterized in that the compound is 3- [5,7-dimethoxy-3- (4-methoxyphenyl) -2-oxo-l, 2-dihydro-l-quinolyl] propanenitrile.

15. Composition according to claim 12, characterized in that the compound is l- [2- (1 H-1,2,3,4-tetrazol-5-yl) ethyl] -5,7-dimethoxy-3- (4-methoxyphenyl) ) -1, 2-d? Hydro-2-quinoline ketone.

16. Composition according to claim 12, characterized in that the compound is N, N-diethyl-3- [5,7-dimethoxy-3- (4-methoxyphenyl) -2-oxo-l, 2-dihydro-l-quinolyl] -propanamide.

17. Compound of formula: characterized because X is selected from = 0, = S and = N-NH-R ', R' is a phenyl or pyridyl group, R1, R2, R "and R4, are independently selected from each other among H, OH, an alkyl group in C? -C4, an alkoxy group in C? -C, an -OCO-R8 group, Re is an alkyl group in C? -C4 / and a group derived from a soda, at least one of the substituents R1, R2 , R3, or R4 qu are different from H, and R2 and R3 can together form a methylenedioxy group. R 5 is a phenyl group or a 1 to 3 phenyl group substituted by groups selected from H, OH, a C 1 -C 4 alkoxy group, a -OCOR 8 group, a phenyl group (C 1 -C 4 alkoxy), a group 0-S02-R'8, R '8 is a C1-C4 alkyl group or a CF3 group, and a group derived from a osa. R5 is selected from H, a C1-C4 alkyl group, a group -CO-R and a group -A-R10, R6a is selected from a group -CO-R9 and a group A-R10, To be an alkylene group in C? -C4. R10 is selected from the 5- or 6-membered heterocyclic groups having 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, the CN group, a group -COOR11, -CONR12R13, a group -NR14R15, and a group- 5 COR16, R11, R12, R13, R14, R15 and R16 which are independently selected from a hydrogen atom, a C 1 -C 4 alkyl group and a phenyl group (C 1 -C 4 alkyl), R 4 and R 5 which can also form together a group -CO-CH2-CH2-, excluding compounds in which X = 0, RS = H and two of the substituents R1, R2, R3, R4 are OH or

18. The compound according to claim 17, characterized in that it is 3- [5,7-dimethoxy-3- (4-methoxyphenyl) -2-oxo-l, 2-dihydro-1-quinolyl] propanenitrile.

19. The compound according to claim 17, characterized in that it is l- [2- (1 H-1,2,3,4-tetrazol-5-yl) ethyl] -5,7-dimethoxy-3- (4- methoxyphenyl) -dihydro-2-quinoline ketone.

20. Compound according to claim 17 which is ** '* -M6 * - * »~ *.« - • «. - • - '- - * > -- ,- , TO - .. ,. > ¿. ..-. -? J ?? t ^ characterized in that it is N, N-diethyl-3- [5,7-dimethoxy-3- (4-methoxyphenyl) -2-oxo-l, 2-dihydro-l-quinolyl] propanamide.

21. Compound of the formula: which is characterized because: X is selected from = 0, = S and = N-NH-R7, R7 is a phenyl or pipdyl group, R1, R2, R3 and R4, are independently selected from each other among H, OH, an alkyl group at C? -C4, an alkoxy group in C? -C4, a group -OCO-R8, RB is an alkyl group in C? -C, and a group derived from a soda, at least one of the substituents R1, R?, R3 , or R4 that are different from H, and R "and R3 can together form a methylenedioxy group. R5 is a phenyl group or a 1 to 3 phenyl group substituted by groups selected from H, OH, an alkoxy group at C? -C, a group -OCOR8, a phenyl group (alkoxy at C? -C4), a group - 0-S0-R '8, R' 8 is an alkyl group at C-C4 or a group CF3, and a group derived from a osa. R6 is selected from a group -A-R1C, To be an alkylene group in C? ~ C4. R10 is selected from the heterocyclic groups of 5 or 6 links having 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, the CN group, a group -COOR11, -CONR12R13, a group -NR14R15, and a group -CR16, R11, R12, R13, R14, R15 and Rlβ which are independently selected from a hydrogen atom, a C?-C4 alkyl group and a phenyl (C enC alkyl) group,

22. Compound of formula: which is characterized because: R1, R2, R3 and R4 are independently selected from each other between H, OH, a C1-C4 alkyl group, a C4-C4 alkoxy group, an -OCO-R8 group, R8 is an alkyl group in C ? ~ C, and a group derived from a bear, at least one of the substituents R1, R2, R3, or R4 that are different from H, and R2 and R3 can together form a methylenedioxy group. RD is a phenyl group or a phenyl group 1 to 3 substituted by groups selected from H, OH, an alkoxy group in C? -C4, a group -OCOR5, a phenyl group (alkoxy in C? -C4), a group -0-SO_-R'8, R 'b is an alkyl group in C1-C4 15 or a CF group and a group derived from a bear .. Roa is selected from a group -COR9, and a group 20 R which is an alkyl group in C? -C4, To be an alkylene group in C? -C. R10 is selected from heterocyclic groups of 25 5 or 6 links having 1 to 4 heteroatoms selected * -J * + - »- -tu *,. TO .. , - . , ».,.». ^ C ^ -.- - ,, .... ._... -,, _, .., < < , i,., between oxygen, sulfur and nitrogen, the CN group, a group -COOR11, -CONR12R13, a group -NR14R15, and a group -COR16, R11, R12, R13, R14, R15 and R16 which are independently selected from a hydrogen atom, a C en-C4 alkyl group and a phenyl (C alquilo-C) alkyl group,