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    • 专利摘要:
    The present invention relates to a pharmaceutical composition comprising an effective amount of a compound selected among the compounds of formula (I) and formula (Ia), wherein: R 1, R 2, R 3, R 4, R 5, R 6 and R < 7 > are as defined in claim 1. These compounds have interesting cytotoxic properties that lead to their use in therapy as anticancer drugs.
    公开号:KR20020056883A
    申请号:KR1020027001753
    申请日:2000-08-11
    公开日:2002-07-10
    发明作者:이블린 델포우른；프란시스 다로；쟝 바스티드；로버트 키스；아르망 프리드만
    申请人:파.세 라퐁；라보라뜨와르 엘르 라퐁；
    IPC主号:
    专利说明:

    Phenanthroline-7-one derivatives and their use in therapy {Phenanthroline-7-one derivatives and their therapeutic uses}
    [2] In 1999, cytotoxic treatment was used to reduce the size of cancerous tumors, or to inhibit the progression of tumor processes or, in a few cases, to eliminate the risk of tumor and metastasis of cancerous cells Chemotherapy) have been combined with other chemicals that have been used for decades and recently introduced chemicals. For example, 5-fluorouracil (5-Fu), known for nearly 40 years as one of the most effective remedies for colorectal cancer, is a topoisomerase I when the tumor is no longer sensitive to 5-Fu (irinotecan or topotecan) by one or the other of the specific inhibitors. More generally, the accumulation of therapies that are available for the treatment of colorectal cancers is the efficacy of oxaliplatin, a new in-situ " donor " of selective inhibitors of 5-Fu or thymidylate synthase As well. Such coexistence is not limited to the treatment of colorectal cancer, and chemotherapy of breast, ovary and lung cancer now makes extensive use of the family of taxane derivatives (paclitaxel and docetaxel). Improvement of the quality of life and survival of the patients is essential, so more effective and well tolerated treatment is needed. For example, in colorectal carcinoma cases, more than 131,000 new cases were diagnosed in 1997 in the US alone, and 54,000 of these were expected to result in patient deaths (SL Parker, T. Tong, S. Bolden et al., CA Cancer J. Clin., 1997). Recognizing this situation, the present inventors have developed a new field of pharmaceutical chemistry, so that in order to allow selection of synthetic compounds derived from chemical design / regulatory studies and imparted with considerable therapeutic cytotoxic activity, attention was focused on polyaromatics identified in seaweeds (warm seas).
    [3] The oceans and oceans that cover more than 70% of the world's surface are home to seabed and sponges, and progressive, organized natural pharmacology studies of them include complex alkaloids with beneficial pharmacological properties of these living species . For example, the surface of the sea crypto teka creep other (Cryptotheca Crypta) and Harley mitochondrial ohkadayi (Halichondria okadai) has been the presence of cytarabine (cytarabin) or Harley cone gave B (halichondrin B) within their cells detected closer study . This has been the subject of research as aplidine has been isolated from the perianal Aplidium albicans in Balearic Island, Spain. The alkaloids of the tetrahydroisoquinolone structure are separated from the Ecteinascidia turbinata in seaweed. Of these, extrenoxynein-743 has been implicated in a careful incubation study (E. Igbicka et al., NCI-EORTC Symposium, 1998; Abst. 130, p. 34) and anticancer drugs (A. Bowman et al., NCI-EORTC Symposium, NCI-EORTC Symposium 1998, Abst. 455, p. 119, E. Citkovic < RTI ID = 0.0 > Etc., NCI-EORTC Symposium, 1998; Abst. 456, p. 119). New pentacyclic acridine derivatives have also been the subject of drug chemistry research (DJ Hagan et al., J. Chem. Soc., Perkin Transf., 1997; 1: 2739-2746).
    [4] The ASCII dideoxy civil alkaloids of other natural ocean origin (ascididemin) is tunicate (tuincate) dideoxy titanium species (Didemnum sp: J Kobayashi, etc., Tetrahedron Lett, 1998; 29: ... 1170 ~ 1180) , and seaweeds in (ascidian ( Cystodytes dellechiajei : I. Bonnard et al., Anti-cancer Drug Design, 1995; 10: 333-346 ). Ascididemin is known to be produced by FJ Schmitz et al. (J. Org. Chem. 1991; 56: 804-808), B. Lindsay et al (Bioorg Med. Chem. Lett., 1995; (P388 or L1210 strain) model and I. Bonnard et al. (Anti-cancer Drug Design, 1995; 10: 336-346) described by Kobayashi et al. (Tetrahedron Lett., 1988; 29: Have demonstrated antiproliferative properties as models of human leukemia described by < RTI ID = 0.0 > S. < / RTI > It has also been isolated from Leptoclinides sp. By seaweed by SJ Bloor et al. (J. Am. Chem. Soc., 1987; 109: 6134 ~ 6136), and F. Bracher et al. (Heterocycles, 1989; 29 : 2093-2095) and then 2-bromoreptoclinidone synthesized by ME Jung et al. (Heterocycles, 1994; 39; 2: 767-778) can be mentioned. 2-bromoreptoclinidone exhibits narrow toxicity to the leukemia cell model with an ED 50 of 0.4 μg / ml. The cytotoxicity was assessed by culturing 60 tumor cell lines in vitro and human tumor cell lines (colonic tumors SW-620 and HTC116, renal tumor A498 and melanoma LOX IM VI) in vivo in mice It was identified by F. Bracher (Pharmazie, 1997; 52: 57-60) as a model of xenograft.
    [5] Such as, for example, 1-hydroxyisoxydamine, 11-methoxyacidyldimine, 11-phenylacididomine, 11-nitrophenylacididemine, 1-nitroasquidodimine, 3-nitroaschedidemine and neokaliactin Other compounds derived from < RTI ID = 0.0 > (Tetrahedron Lett., 1997; 53: 17029-17038), G. Gellerman et al., (1994) (Tetrahedron Lett., 1993; 34: 1827-1830), S. Nakahara et al. (Heterocycles, 1993; 36: 1139-1144) and I. Spector et al. (US-A 5 432 172) .
    [6] Meridin is another natural alkaloid extracted from the seaweed Amphicarpa meridiana or from the sea bed, Corticum sp . Meridin was isolated by FJ Schmitz et al. (J. Org. Chem., 1991; 56: 804-808) and thereafter was characterized by antiproliferative properties in rat leukemia model (P388) and patent US 5 182 287 The cytotoxic properties of two human cell lines, colon cancer cells (HT-29) and lung carcinoma cells (A549) were examined by RE Longley (J. of Nat. Products, 1993; 56: 915-920).
    [7] Among these compounds, mention may be made of the cysteide amines , the pentacyclic alkaloids separated from the seaweed Cystodytes dellechiajei by N. Bontemps et al. (Tetrahedron Lett., 1994; 35: 7023-7026 ) , Indicating cytotoxic activity against human leukemic lymphocytes.
    [1] The present invention relates to pharmaceutical compositions based on polyaromatic compounds useful as anticancer drugs.
    [8] The subject of the present invention are the compounds of the following general formulas I and la and their pharmaceutically acceptable acid addition salts:
    [9]
    [10] From here,
    [11] Wherein R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl groups, hydroxyl, -CHO, -OR 8 , -COOH, -CN, -CO 2 R 8 , CONHR 8, -CONR 8 R 9, -NH 2, -NHR 8, -N (R 8) 2, -NH-CH 2 -CH 2 -N (CH 3) 2, -NH-CH 2 -CH 2 - Cl, -NHCOR 8 , morpholino, nitro, SO 3 H, ≪ / RTI >
    [12] R 8 and R 9 are selected from C 1 -C 6 alkyl groups and phenyl (C 1 -C 4 ) alkyl groups, Ar is selected from C 6 -C 14 aryl groups,
    [13] R 6 is selected from hydrogen, halogen, C 1 -C 6 alkyl or R 10 is selected from halogen or -OH, (C 1 -C 6 ) alkoxy or -O-CO- (C 1 -C 6 ) n is selected from the group consisting of - (CH 2 ) n R 10 groups, -CN, CO 2 Et, or -COR 11 groups wherein R 11 is selected from C 1 -C 6 alkyl or phenyl (C 1 -C 4 ) (C 1 -C 6 ) alkoxy and -N (CH 3 ) 2 groups, wherein R 12 and R 13 are hydrogen or C 1 -C 6 alkyl, phenyl (C 1 -C 4 ) alkyl or R 14 is halogen And n is selected from -NR 12 R 13 groups independently selected from the group - (CH 2 ) n R 14 where n is 1 to 6,
    [14] R 7 is hydrogen, (C 1 ~ C 6) alkyl, phenyl (C 1 ~ C 4) alkyl, R 15 and R 16 is hydrogen, C 1 ~ C 6 alkyl and phenyl (C 1 ~ C 4) alkyl type (CH 2 ) n wherein n is selected from 1 to 6, -NR 15 R 16 , wherein R 17 is selected from hydrogen, halogen or -OH or a (C 1 -C 6 ) alkoxy group, R < 17 & gt ;.
    [15] Particular groups of compounds of the general formula I and / or Ia are:
    [16] Wherein R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl groups, hydroxyl, -CHO, -OR 8 , -COOH, -CN, -CO 2 R 8 , CONHR 8 , -CONR 8 R 9 , -NH 2 , -NHR 8 , -N (R 8 ) 2 , -NH-CH 2 -CH 2 -N (CH 3 ) 2 , -NHCOR 8 , morpholino, SO 3 H, ≪ / RTI >
    [17] R 8 and R 9 are selected from C 1 -C 6 alkyl groups and Ar is selected from C 6 -C 14 aryl groups.
    [18] The subject matter of the present invention is more particularly a compound selected from compounds of general formula (I) and general formula (Ia) and pharmaceutically acceptable acid addition salts thereof: wherein R 1 , R 2 , R 3, R 4 and R 5 is hydrogen, halogen, C 1 ~ C 6 alkyl, hydroxyl, -OR 8, -NO 2, -NH 2, -NHR 8, -NH (R 8) 2, -NH- CH 2 -CH 2 -N (CH 3 ) 2, -NH-CH 2 -CH 2 -Cl, selected from -NHCOR 8, R 8 is selected from C 1 ~ C 6 alkyl group,
    [19] R 6 is hydrogen, R 10 is selected from halogen, -O-CO-CH 3 group - (CH 2) n R 10 groups, C 1 ~ C 6 alkyl group and, R 12 and R 13 is hydrogen or C 1 - a C 6 alkyl, benzyl, or R 14 is selected from halogen or (C 1 - C 6) alkoxy and -N (CH 3) 2 groups, n is 1 to 6 - from (CH 2) n R 14 groups is selected from the -N (R 12 R 13) independently selected groups,
    [20] R 7 is selected from the group consisting of hydrogen or (C 1 -C 6 ) alkyl-type groups, benzyl, -N (R 15 R 16 ), and R 15 and R 16 are selected from hydrogen and C 1 -C 6 alkyl- , R 17 is selected from hydrogen, halogens or -OH or (C 1 ~ C 6) alkoxy groups, n is 1 to 6 - is selected from (CH 2) n R 17.
    [21] The group of preferred compounds consists of the general formulas I and Ia in which at least one of the R 1 , R 2 , R 3 , R 4 and R 5 groups is an OR 8 group.
    [22] The expression " pharmaceutically acceptable acid addition salts " refers to salts which provide the biological properties of free bases without adverse effects. In particular, these salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid; Disodium orthophosphate and monopotassium sulfate, and organic acids.
    [23] In general, the compounds of formulas (I) and (Ia) can be obtained by a process comprising the following steps:
    [24] a) In order to obtain a mixture of the compounds of the general formula II and the general formula IIa according to the Diels-Alder reaction, a quinolinedione of the general formula IV and an azadiene of the general formula V, in which X = CH 3 )
    [25]
    [26]
    [27]
    [28] b) optionally isolating the compound of formula II and IIa,
    [29] c 1 ) In order to obtain the enamines of the general formula III and / or IIIa, the general formula II and / or IIa is reacted with dimethylformamide dimethylacetal in succession, and then to introduce the R 6 and / or R 7 substituent Functionalizing the enamine and cyclizing it to obtain a compound of the general formula I and / or Ia, or
    [30]
    [31] c 2 ) simultaneously functionalizing and cyclizing to obtain a compound of formula I and / or Ia,
    [32] d) optionally separating the compounds of general formula I and la.
    [33] In another aspect, compounds of general formula I or la in which R < 6 > and R < 7 > are hydrogen can be obtained by a process comprising the following steps:
    [34] a) step of in order to obtain a mixture of formula II with the compounds of IIa, reacting an aza-diene of the general formula IV and formula V (wherein, X = CH 2 -CH 2 -NHBoc ),
    [35]
    [36]
    [37]
    [38] b) optionally isolating the compound of formula II and IIa,
    [39] c) cyclizing the compound of general formula II and / or IIa to obtain a compound of general formula I and / or Ia,
    [40] d) optionally isolating the compound of formula I or la.
    [41] The reaction for the cyclization of the compounds of the general formulas III and IIIa can be carried out in the presence of hot conditions in the presence of NH 4 Cl in a suitable solvent.
    [42] When X = CH 2 -CH 2 -NHBoc, the compounds of general formula I and Ia are obtained directly from the compounds of general formulas II and IIa in the presence of NaHCO 3 in trifluoroacetic acid medium.
    [43] The functionalization for the introduction of the R 6 substituent is carried out in the presence of an induced reactant such as R-COCl, ClCN, ClCO 2 Et, ClCH 2 OR, FClO 3 or CH 2 ═N + (CH 3 ) 2 I - (in CH 3 COOH) . ≪ / RTI >
    [44] Functionalization for the introduction of an R 7 substituent can be accomplished by Mannich reaction with an aldehyde of the general formula R 7 -CHO.
    [45] In this case, simultaneous cyclization can be effected in the presence of excess ammonium chloride in acetic acid.
    [46] Examples of substituted azadiene may be prepared according to the following reaction scheme:
    [47]
    [48] TEMPO = tetramethyl-1-piperidinyloxy, free radical
    [49] TBACl = tetrabutylammonium chloride
    [50] FMTP = formylmethylenetriphenylphosphorane
    [51] The following examples illustrate the preparation of compounds of formula (I) and (Ia).
    [52] Preparation of A-azadiene (Compound 4)
    [53] A-1 - Synthesis of N-Boc-1-amino-2-hydroxypropane (Compound 1)
    [54] 4.2 g (29.7 mmol) of di-t-butyl dicarbonate are added to a solution of 2 ml (27 mmol) of 3-amino-1-propanol in a mixture of 60 ml of dioxane, 30 ml of water and 30 ml of 1N NaOH at 0 ° C . The reaction mixture was stirred overnight at ambient temperature and then acidified to pH 1 using concentrated HCl. After a few times extracted with ethyl acetate (AcOEt) (3 times 50ml), the organic phase was dried with MgSO 4, and concentrated by rotary evaporation to give the expected product was of 4g in the form of a yellow oil.
    [55]
    [56] A-2 - Synthesis of N-Boc-3-aminopropane (Compound 2)
    [57] (10.4 mmol) of TEMPO (tetramethyl-1-piperidinyloxy, free radical), 2.9 g (10.45 mmol) of tetrabutylammonium chloride and 21 g (75.5 mmol) of N -Chlorosuccinimide was suspended in 351 ml of NaHCO 3 / K 2 CO 3 (0.5 N / 0.05 N) and 351 ml of CHCl 3 . The reaction mixture was vigorously stirred for 2 hours. After the organic phase is separated by settling, dried with MgSO 4, to give the aldehyde which was concentrated by rotary evaporation expected in the form of a light orange oil.
    [58]
    [59] A-3 - N-Boc-5-amino-2-penten-1-yl (Compound 3)
    [60] 11 g (66.7 mmol) of Compound 2 and 24.3 g (80 mmol) of formylmethyltriphenylphosphorane (FMTP) were dissolved in 350 ml of benzene and the reaction mixture was refluxed for 9 hours. After evaporation of the solvent on a rotary evaporator to thereby remove the first filter [(1/1 CHCl 3 / heptane), followed by CHCl 3 to - triphenylphosphine to the residue through silica. Second filtration through silica gave 3.88 g of compound 3 in the form of an orange-yellow oil.
    [61]
    [62] A-4 - N-Boc-5-amino-2-pentene-1-aldimethylhydrazone (Compound 4)
    [63] 3.88 g (19.5 mmol) of compound 3 were added at 0 < 0 > C to 1.47 ml (1.95 mmol) of dimethylhydrazine and 8 drops of acetic acid in 30 ml of ether. The reaction mixture was left to stir for 10 minutes, the organic phase was separated by precipitation, washed with 1N HCl and then with saturated NaCl solution. After drying over MgSO 4 , the solvent was evaporated in a rotary evaporator to give 4.4 g of hydrazone (Compound 4) in the form of an orange-yellow oil.
    [64]
    [65] B - Preparation of compounds of formula II and IIa
    [66] B-1: 4-Methylpyrido [2,3-g] quinolin-5,10-dione (Intermediate I-1b) and 4-methylpyrido- [3,2-g] quinoline- (Intermediate II-1b)
    [67] A mixture of 0.5 g (3.14 mmol) of quinolin-5,8-dione, 0.35 g (3.14 mmol) of crotonaldehyde dimethyl hydrazone and 0.45 ml (4.76 mmol) of anhydrous acetic acid in 20 ml of CHCl 3 was sonicated in a bath, For 1 hour. After evaporation of the solvent on a rotary evaporator, the reaction mixture was filtered through silica (CHCl 3 ) to give 0.428 g of a mixture of two isomers I-1a and II-1a in the form of a purple powder. This powder and 1.6 g (18.4 mmol) of MnO 2 were suspended in 20 ml of CHCl 3 and the mixture was refluxed for 2 hours. After filtration through celite, the filtrate was concentrated in a rotary evaporator and then purified by flash chromatography on silica column (98/2 CH 2 Cl 2 / MeOH) to give the following compound:
    [68] Intermediate (I-1b): 4-Methylpyrido [2,3-g] quinoline-5,10-dione
    [69]
    [70] Intermediate (II-1b): 4-Methylpyrido [3,2-g] quinoline-5,10-dione
    [71]
    [72] B-2: Synthesis of 9-methoxy-4-methylpyrido [2,3-g] quinoline-5,10-dione (Intermediate I- g] quinoline-5,10-dione (Intermediate II-2b)
    [73] A mixture of 0.5 g (2.8 mmol) of 4-methoxyquinoline-5,8-dione, 0.32 g (2.87 mmol) of crotonaldehyde dimethylhydrazone and 0.4 ml (4.23 mmol) of anhydrous acetic acid in 8 ml of CHCl 3 was treated with 1 Lt; / RTI > After evaporation of the solvent on a rotary evaporator, the reaction mixture was filtered through silica (98/2 CH 2 Cl 2 / MeOH) to give 0.48 g of a mixture of two isomers I-2a and II-2a in the form of a purple powder. This powder and 2.3 g (26.45 mmol) of MnO 2 were suspended in 26 ml of CHCl 3 and the mixture was refluxed for 2 hours. After filtration through celite, the filtrate was concentrated in a rotary evaporator and then purified by flash chromatography on silica column (98/2 CH 2 Cl 2 / MeOH) to give the following compound:
    [74] Intermediate I-2b: 9-Methoxy-4-methylpyrido [2,3-g] -quinoline-5,10-dione
    [75]
    [76] Intermediate II-2b: 6-Methoxy-4-methylpyrido [3,2-g] -quinoline-5,10-dione
    [77]
    [78] B-3: Synthesis of 9-nitro-4-methoxypyrido [2,3-g] quinoline-5,10-dione (Intermediate I- ] Quinoline-5,10-dione (Intermediate II-5b)
    [79] A mixture of 0.8 g (3.92 mmol) of 4-nitroquinolin-5,8-dione, 0.65 g (5.8 mmol) of crotonaldehyde dimethylhydrazone and 0.55 ml (5.8 mmol) of anhydrous acetic acid in 10.5 ml of CHCl 3 was added to 30 Min in an ultrasonic bath. After evaporation of the solvent in a rotary evaporator, the reaction mixture was filtered through silica (98/2 CH 2 Cl 2 / MeOH) to give 0.7 g of a mixture of two isomers I-5a and II-5a in the form of a purple powder. This powder and 2.9 g (33.4 mmol) of MnO 2 were suspended in 29 ml of CHCl 3 and the mixture was refluxed for 2 hours. After filtration through celite, the filtrate was concentrated in a rotary evaporator and then purified by flash chromatography on silica column (98/2 CH 2 Cl 2 / MeOH) to give the following compound:
    [80] Intermediate I-5b: 9-Nitro-4-methylpyrido [2,3-g] quinoline-5,10-dione
    [81]
    [82] Intermediate II-5b: 6-Nitro-4-methylpyrido [3,2-g] quinoline-5,10-dione
    [83]
    [84] B-4: 9-Dimethylamino-4-methylpyrido- [2,3-g] quinoline-5,10-dione (Intermediate I- -g] quinoline-5,10-dione (Intermediate II-3b)
    [85] 150 mg (0.558 mmol) of nitrated tricyclic I-5a or II-5a and 0.4 ml (1.95 mmol) of N, N-dimethylformamide diethyl acetal are dissolved in 2.1 ml of DMF, And heated for 1 hour. After evaporation of the solvent with a vacuum pump, 140 mg of intermediate compound II-3a or II-3b were obtained, which material was used as such in the next step:
    [86] Intermediate II-3b: 6-Dimethylamino-4-methylpyrido- [3,2-g] quinoline-5,10-dione
    [87]
    [88] B-5: 9-Chloro-4- (N-Boc-1-amino-ethane) -5,10-dihydropyrido [2,3-g] quinoline- 5,10-dione (Intermediate I- (Intermediate II-7b) was synthesized in the same manner as in Example 1, except that 6-chloro-4- (N-Boc-1-aminoethanen-5,10-dihydropyrido [
    [89] A mixture of 0.6 g (3.1 mmol) of 4-chloroquinolin-5,8-dione, 0.75 g (3.1 mmol) of dimethylhydrazone 4 and 0.45 ml (4.76 mmol) of anhydrous acetic acid in 8.5 ml of CHCl 3 was stirred for 30 minutes Lt; / RTI > After evaporation of the solvent in a rotary evaporator, 2.7 g (31.1 mmol) of MnO 2 and 22 ml of CHCl 3 were added to the reaction mixture and refluxed for 2 hours. After filtration through celite, the filtrate was concentrated in a rotary evaporator and then purified by flash chromatography on silica column (99/1 CH 2 Cl 2 / MeOH) to give the following compounds:
    [90] Intermediate I-7b: 9-Chloro-4- (N-Boc-1-aminoethane) -5,10- dihydropyrido [2,3-g] quinoline-5,10-
    [91]
    [92] Intermediate II-7b: 6-Chloro-4- (N-Boc-1-aminoethanen-5,10-dihydropyrido [3,2-g] quinoline-
    [93]
    [94] B-6: Synthesis of 3-methoxy-4-methylpyrido [2,3-g] quinoline-5,10-dione (Intermediate I- g] quinolin-5,10-dione (Intermediate II-8b)
    [95] A mixture of 2-methoxy-2-part tenal dimethyl hydrazone of quinoline-5,8-dione and 1.78g (12.57mmol) of 1g (6.28mmol) in 25ml of CHCl 3 was stirred at ambient temperature for 5 minutes. After evaporation of the solvent on a rotary evaporator, the reaction mixture was filtered through silica (95/5 CH 2 Cl 2 / MeOH) to give 1.55 g of a mixture of two isomers I-8a and II-8a in the form of a purple powder. This powder and 1 g (11.5 mmol) of MnO 2 were suspended in 30 ml of CHCl 3 and the mixture was stirred at ambient temperature for 1 hour. After filtration through celite, the filtrate was concentrated in a rotary evaporator and then purified by flash chromatography on silica column (99/1 CH 2 Cl 2 / MeOH) to give the following compounds:
    [96] Intermediate I-8b: 3-Methoxy-4-methylpyrido [2,3-g] quinoline-5,10-dione
    [97]
    [98] Intermediate II-8b: 3-Methoxy-4-methylpyrido [3,2-g] quinoline-5,10-dione
    [99]
    [100] B-7: Synthesis of 3,9-dimethoxy-4-methylpyrido [2,3-g] quinoline-5,10-dione (Intermediate I-9b) and 3,6-dimethoxy- 3,2-g] quinolin-5,10-dione (Intermediate II-9b)
    [101] A solution of 2-methoxy-2-butenal dimethylhydrazone (1 g, 7.1 mmol) in 15 ml of chloroform was added dropwise to a solution of 4-methoxyquinolin dione (1.33 g, 7 mmol) in 30 ml of chloroform. The reaction mixture was stirred under a nitrogen atmosphere at ambient temperature for 5 hours with interception of light. After evaporation of the solvent on a rotary evaporator and the resulting crude product is non-aromatic (nonaromatic) was purified by flash chromatography over silica to produce a second fraction F 2 containing the first fraction F 1 and the expected product which comprises the product (CHCl 3 , then 98/2 CHCl 3 / MeOH, then 95/5 CHCl 3 / MeOH). 1 g of MnO 2 was added to the fraction F 1 and 30 ml of chloroform. The mixture was left to stir for 90 minutes. After filtration through celite, the precipitate was washed with CHCl 3 , then with MeOH, and the filtrate was concentrated on a rotary evaporator to produce fraction F 1 '. The combined fractions F 1 'and F 2 were then purified by flash chromatography over silica (CHCl 3 followed by 97/3 CHCl 3 / MeOH) to give two expected compounds I-9b And II-9b.
    [102] Intermediate (II-9b): 3,6-Dimethoxy-4-methylpyrido- [3,2-g] quinoline-5,10-dione
    [103]
    [104] B-8 - (Intermediate I-10b) and 3-methoxy-4-methyl-6-chloropyrido [3,2-g] quinolin-5,10-dione (Intermediate II-10b)
    [105] A solution of 2-methoxy-2-butenal dimethylhydrazone (1 g, 7.1 mmol) in 15 ml of chloroform was added dropwise to a solution of 4-chloroquinolin dione (1.37 g, 7.1 mmol) in 30 ml of chloroform. The reaction mixture was stirred under a nitrogen atmosphere at ambient temperature for 5 hours and 30 minutes while blocking the light. The crude product obtained after evaporation of the solvent in a rotary evaporator was purified by flash chromatography on silica (CHCl 3 followed by 98/2 CHCl 3 / MeOH) to yield a primary fraction F 1 containing non-aromatic products Lt; / RTI > 1 g of MnO 2 was added to this fraction F 1 and 30 ml of chloroform. The mixture was left to stir for 60 minutes. After filtering through Celite, the precipitate washed with CHCl 3, and then washed with MeOH, and the mixture is concentrated on a rotary evaporator. The resulting crude product was purified by flash chromatography on silica (97/3 (lacuna)) to give compounds I-10b and II-10b in the form of a yellow powder.
    [106] Intermediate II-10b: 3-Methoxy-4-methyl-6-chloropyrido- [3,2-g] quinoline-
    [107]
    [108] B-9: Synthesis of 3-methoxy-4-methyl-9-dimethyl-aminopyrido [2,3-g] quinoline-5,10-dione (Intermediate I- Synthesis of 6-dimethylaminopyrido [3,2-g] quinoline-5,10-dione (Intermediate II-11b)
    [109] A solution of THF / H 2 O I-10b or II-10b (90mg, 0.31mmol) in a mixture of (4ml / 2ml), ammonium chloride (127mg, 1.56mmol) and NaOH (63mg, 1.56mmol) for 1 hour Lt; / RTI > After evaporation of the solvent in a rotary evaporator, the resulting crude product was dissolved in a 95/5 CH 2 Cl 2 / MeOH mixture (50 ml). After recovering the organic phase it was dried over MgSO 4. After concentration on a rotary evaporator, the resulting crude product was purified by flash chromatography on silica (95/5 CH 2 Cl 2 / MeOH) to give the expected compound I-11b or II-11b in the form of a yellow powder.
    [110] Intermediate II-11b: 3-Methoxy-4-methyl-6-dimethyl-aminopyrido [3,2-g] quinoline-
    [111]
    [112] B-10: Synthesis of 3,7-dimethoxy-4-methylpyrido- [2,3-g] quinoline-5,10-dione (Intermediate I-12b) and 3,8-dimethoxy- - [3,2-g] quinolin-5,10-dione (Intermediate II-12b)
    [113] One - Synthesis of 2-methoxyquinoline-5,8-dione
    [114] A suspension of 5,8-dioxocarbostyril (3.1 g, 17.7 mmol), silver carbonate (10.2 g, 37 mmol) and methyl iodide (31 ml, 498 mmol) in 1.2 L of CHCl 3 was added dropwise at ambient temperature And stirred for 90 hours. The precipitate was filtered off and the filtrate was concentrated in a rotary evaporator. The obtained crude product was purified by filtration (CHCl 3) over silica to give a quinone expected in the form of a yellow solid (2.2g).
    [115]
    [116] 2 - Dimethoxy-4-methylpyrido- [2,3-g] quinoline-5,10-dione (Intermediate I-12b) and 3,8- -g] quinoline-5,10-dione (Intermediate II-OneSynthesis of 2b)
    [117] A solution of 2-methoxy-2-butanedimethylhydrazone (0.75 g, 5.3 mmol) in 10 ml of THF was added dropwise to a solution of methoxyquinolin dione (1.0 g, 5.3 mmol) in 60 ml of THF. The reaction mixture was stirred under a nitrogen atmosphere at ambient temperature for 40 hours with blocking of light. After evaporation of the solvent in a rotary evaporator, the resulting crude product was dissolved in 80 ml CHCl 3 and 85% MnO 2 (5.4 g, 53 mmol) was added. The reaction mixture was stirred for 2 hours and then filtered through celite. The crude product obtained after concentrating on a rotary evaporator was purified by flash chromatography (CHCl 3 ) through silica to give compounds I-12b and II-12b in the form of a brown powder.
    [118] Intermediate II-12b: 3,8-Dimethoxy-4-methylpyrido- [3,2-g] quinoline-5,10-dione
    [119]
    [120] B-11: Preparation of 8-methoxycarbonyl-8- (2'-N-Boc-aminoethyl) pyrido [2,3-g] quinoline-5,10-dione (Intermediate I- Synthesis of carbonyl-6- (2'-N-Boc-aminoethyl) pyrido [3,2-g] quinolin-5,10-dione (Intermediate II-13b)
    [121] A solution of N-Boc-5-amino-2-pentene-1-aldimethylhydrazone (1.1 g, 4.56 mmol) in 15 ml of acetonitrile was added dropwise to a solution of 3-ethyl cyquinolinecarboxylate -Dione (1.05 g, 4.54 mmol) and anhydrous acetic acid (4.6 ml). The reaction mixture was stirred under a nitrogen atmosphere at ambient temperature for 24 hours with blocking of light. After evaporation of the solvent in a rotary evaporator, 5 g of MnO 2 and 150 ml of chloroform were added to the crude product obtained. The mixture was left stirring at ambient temperature for 1 hour 30 minutes. After filtration through celite, the precipitate was washed with CHCl 3 , then with MeOH, and the mixture was concentrated on a rotary evaporator. The crude product obtained was first purified by filtration through silica (99/1, then 97/3 CHCl 3 / MeOH), then purified by flash chromatography on silica (99/1) to give the form of brown powder To obtain compounds I-13b and II-13b.
    [122] Intermediate II-13b: 7-Ethoxycarbonyl-6- (2'-N-Boc-aminoethyl) pyrido [3,2-g] quinoline-
    [123]
    [124] B-12: 7-Hydroxy-4- (2'-N-Boc-aminoethyl) -pyrido [2,3-g] quinoline- 5,10-dione (Intermediate I- (2'-N-Boc-aminoethyl) pyrido [3,2-g] quinoline-5,10-dione (Intermediate II-14b)
    [125] A solution of N-Boc-5-amino-2-pentene-1-aldimethylhydrazone (1.49 g, 6.15 mmol) in 30 ml of acetonitrile was added to a solution of 5,8-dioxocarbostyril , 5.59 mmol) and anhydrous acetic acid (5.8 ml). The reaction mixture was stirred under a nitrogen atmosphere at ambient temperature for 16 hours with blocking of light. After evaporation of the solvent in a rotary evaporator, 7 g (80.5 mmol) of MnO 2 and 180 ml of chloroform were added to the resulting crude product. The mixture was left stirring at ambient temperature for 1 hour 30 minutes. After filtration through celite, the precipitate was washed with CHCl 3 , then with MeOH, and the mixture was concentrated on a rotary evaporator. The resulting crude product was purified by filtration through silica (98/2 then 95/5 CH 2 Cl 2 / MeOH) to give compounds I-14b and II-14b in the form of a brown powder.
    [126] Intermediate II-14b: 8-Hydroxy-4- (2'-N-Boc-aminoethyl) -pyrido [3,2-g] quinoline-
    [127]
    [128] B-13: Preparation of 7-hydroxy-4-methylpyrido [2,3-g] quinoline-5,10-dione (Intermediate I- g] quinoline-5,10-dione (Intermediate II-15b)
    [129] A solution of 2-butenal dimethylhydrazone (0.703 g, 6.28 mmol) in 20 ml of acetonitrile was added to a solution of 5,8-dioxocarbostyril (1 g, 5.71 mmol) and anhydrous acetic acid Was added dropwise to the solution. The reaction mixture was stirred under a nitrogen atmosphere at ambient temperature for 16 hours while shaking the light, and then refluxed for 6 hours. After evaporation of the solvent in a rotary evaporator, the resulting crude product was purified by filtration through silica (CH 2 Cl 2 followed by 98/2 CH 2 Cl 2) to yield a primary fraction containing the nonaromatic and expected product / MeOH). ≪ / RTI > 3 g of MnO 2 and 75 ml of chloroform were added to the mixture and the mixture was left stirring at ambient temperature overnight. After filtering through Celite, the precipitate washed with CHCl 3, and then washed with MeOH, and the mixture is concentrated on a rotary evaporator. The resulting crude product was purified by flash chromatography (99/1) through silica to give the expected compounds I-15b and II-15b in the form of a beige powder.
    [130] Intermediate II-15b: 8-Hydroxy-4-methylpyrido [3,2-g] quinoline-5,10-dione
    [131]
    [132] B-14: Synthesis of 7-methoxy-4-methylpyrido [2,3-g] quinoline-5,10-dione (Intermediate I- g] quinoline-5,10-dione (Intermediate II-16b)
    [133] A mixture of compound I-15b or II-15b (70 mg, 0.29 mmol), methyl iodide (1 ml, 15.9 mmol) and Ag 2 CO 2 (170 mg, 0.62 mmol) in 100 ml CHCl 3 was stirred at ambient temperature for 14 hours The mixture was stirred while blocking light, and then heated at 56 DEG C for 5 hours. The crude product obtained after concentrating on a rotary evaporator was purified by flash chromatography (99.5 / 0.5 CH 2 Cl 2 / MeOH) on silica to give the expected compound I-16b or II-16b in the form of a beige-brown powder.
    [134] Intermediate II-16b: 8-Methoxy-4-methylpyrido [3,2-g] quinoline-5,10-dione
    [135]
    [136] B-15: Synthesis of 7,9-dichloro-4-methylpyrido- [2,3-g] quinoline-5,10-dione (Intermediate I- 3,2-g] quinolin-5-y-dione (Intermediate II-17b)
    [137] One. Synthesis of 2,4-dichloroquinoline-5,8-dione
    [138] To a solution of cerium ammonium nitrate (CAN 21.4g, 39.03mmol) a CH 3 CN / H 2 O mixture (150ml / 75ml) 2,4- dichloro-5,8-dimethoxy-quinoline (2.85g, 11.04mmol) in Lt; / RTI > The reaction mixture was stirred at ambient temperature for 40 minutes. Thereafter, the acetonitrile was evaporated, added to a saturated NaHCO 3 in 50ml of water and 200ml. The aqueous phase was extracted with CH 2 Cl 2 (5 times 200 ml). After drying over MgSO 4 , the solvent was evaporated in a rotary evaporator to give the expected compound in the form of a brown powder (1.9 g).
    [139]
    [140] 2. Dichloro-4-methylpyrido [2,3-g] quinoline-5,10-dione (Intermediate I-17b) and 6,8- Synthesis of quinolin-5,10-dione (Intermediate II-17b)
    [141] A solution of 2-butenal dimethylhydrazone (0.325 g, 2.89 mmol) in 20 ml of acetonitrile was added to a solution of 2,4-dichloroquinoline-5,8-dione (0.6 g, 2.63 mmol) and acetic anhydride 5 ml) was added dropwise. The reaction mixture was stirred under a nitrogen atmosphere at ambient temperature for 20 hours with blocking of light. After evaporation of the solvent on a rotary evaporator, dissolve the crude product obtained in CHCl 3 of 140ml. Thereafter, the mixture around the addition of MnO 2 of 3.65g, and then the temperature was left to stir for 56 hours. After filtration through celite, the precipitate was washed with CHCl 3 , then with MeOH, and the solution was concentrated on a rotary evaporator. The resulting crude product was purified by flash chromatography (CH 2 Cl 2 ) through silica to give the expected compounds I-17b and II-17b in the form of a brown powder.
    [142] Intermediate II-17b: 6,8-Dichloro-4-methylpyrido [3,2-g] quinoline-5,10-dione
    [143]
    [144] Methoxy-4-methylpyrido- [2,3-g] quinoline-5,10-dione (Intermediate I-18b) and 6,8- [3,2-g] quinoline-5,10-dione (Intermediate II-18b)
    [145] A mixture of Compound I-17b or Compound II-17b (80 mg, 0.27 mmol) in 40 ml of methanol and sodium methoxide (300 mg Na in 13 ml of methanol, 13.04 mmol) was refluxed for 17 hours. The reaction mixture was concentrated to dryness and then 50 ml of water was added. After neutralization with 25% HCl, the solution was extracted with CH 2 Cl 2 (3 times 50 ml). After drying over MgSO 4 , the solvent was evaporated in a rotary evaporator to quantitatively obtain the expected compound I-18b or II-18b [Rakuna].
    [146] Intermediate II-18b: 6,8-Dimethoxy-4-methylpyrido- [3,2-g] quinoline-5,10-dione
    [147]
    [148] Example 1
    [149] 7H-pyrido [4,3,2-de] [1,10] phenanthroline-7-one (CRL 8293) and 7H-pyrido [ 7-one (CRL 8294)
    [150] 63 mg (2.81 mmol) of compound Ib and 1.7 ml (9.84 mmol) of dimethylformamide diethyl acetal in 4.5 ml of DMF were heated to 120 < 0 > C for 1 hour under a nitrogen atmosphere. After evaporation of the solvent with a vacuum pump, 3.5 g (65 mmol) of NH 4 Cl and 60 ml of anhydrous ethanol were added. The reaction mixture was refluxed for 30 minutes. After evaporation of the ethanol on the rotary evaporator, 50 ml of water was added to the residue and extracted with CH 2 Cl 2 (3 times 50 ml). The organic phase was dried over MgSO 4 and the solvent was evaporated in a rotary evaporator to obtain 0.6 g of CRL 8294 in the form of a greenish powder.
    [151] 7H-pyrido [4,3,2-de] [1,10] phenanthroline-7-one (CRL 8293)
    [152]
    [153] 7H-pyrido [4,3,2-de] [1,7] phenanthroline-7-one (CRL 8294)
    [154] Starting from intermediate II-1b, 72 mg of compound CRL 8294 was obtained in the form of a yellow powder according to the procedure described above.
    [155]
    [156] Example 2
    [157] Methoxy-7H-pyrido [4,3,2-de] [1,10] phenanthroline-7-one (CRL 8363) and 11-methoxy-7H-pyrido [ -de] [l, 7] phenanthroline-7-one (CRL 8364)
    [158] 74 mg (2.92 mmol) of the compound I-2b and 2 ml (11.8 mmol) of dimethylformamide diethyl acetal in 5.2 ml of DMF were allowed to reach 120 占 폚 under a nitrogen atmosphere for 1 hour. After evaporation of the solvent with a vacuum pump, 4.5 g (83.6 mmol) of NH 4 Cl and 67 ml of anhydrous ethanol were added. The reaction mixture was refluxed for 30 minutes. After evaporation of the ethanol on the rotary evaporator, 50 ml of water was added to the residue and extracted with CH 2 Cl 2 (3 times 50 ml). The organic phase was dried over MgSO 4 , the solvent was evaporated in a rotary evaporator and the residue was purified by flash chromatography on silica column (98/2 CHCl 3 / MeOH) to give 0.28 g of compound CRL 8363 in the form of an orange powder .
    [159] 8-methoxy-7H-pyrido [4,3,2-de] [1,10] phenanthroline-7-one (CRL 8363)
    [160]
    [161] 11-methoxy-7H-pyrido [4,3,2-de] [1,10] phenanthroline-7-one (CRL 8364)
    [162] Starting from 1.14 g of intermediate II-2b, 0.59 g of compound CRL 8364 was obtained in the form of a yellow powder according to the procedure described above.
    [163]
    [164] Example 3
    [165] 7H-pyrido [4,3,2-de] [1,10] phenanthroline-7-one (CRL 8800) and 11- (dimethylamino) -7H-pyrido [ , 3,2-de] [1,7] phenanthroline-7-one (CRL 8367)
    [166] 80 mg (0.3 mmol) of tricyclic I-3b or tricyclic II-3b and 0.21 ml (1.05 mmol) of dimethylformamide diethyl acetal in 1.2 ml of DMF were allowed to reach 120 占 폚 under a nitrogen atmosphere for 1 hour. After evaporation of the solvent with a vacuum pump, 0.5 g (9.3 mmol) of NH 4 Cl and 80 ml of anhydrous ethanol were added. The reaction mixture was refluxed for 40 minutes. After evaporation of the ethanol in the rotary evaporator, 5 ml of water was added to the residue and extracted with CH 2 Cl 2 (3 times 5 ml). The organic phase was dried over MgSO 4 and the solvent was evaporated on a rotary evaporator to yield two tetracyclic compounds in the form of red powder quantitatively.
    [167] 7-Pyrido [4,3,2-de] [1,7] phenanthroline-7-one (CRL 8367)
    [168]
    [169] Example 4
    [170] 7H-pyrido [4,3,2-de] [1,10] phenanthroline-7-one (CRL 8802) and 11-hydroxy-7H-pyrido [ -de] [l, 7] phenanthroline-7-one (CRL 8388)
    [171] 50 mg (0.126 mmol) of tricyclic I-7b or trityl II-7b were dissolved in 0.5 ml of TFA and the reaction mixture was stirred for 24 hours. TFA was evaporated on a rotary evaporator and a saturated NaHCO 3 solution was added until a pH of 9-10 was obtained. The mixture was extracted with CH 2 Cl 2 (3 x 3 times). After drying the mixture was MgSO 4, the solvent was evaporated on a rotary evaporator, to give a tetra-cyclic compound of 20mg in the form of a yellow powder.
    [172] Hydroxy-7H-pyrido [4,3,2-de] [1,7] phenanthroline-7-one (CRL 8388)
    [173]
    [174] Example 5
    [175] Chloro-7H-pyrido [4,3,2-de] [1,10] phenanthroline-7-one (CRL 8396) and 11-chloro-7H- ] [1,7] phenanthroline-7-one (CRL 8801)
    [176] After 260 mg (0.67 mmol) of tricyclic I-7b or trityl II-7b were dissolved in 2.6 ml of TFA, the reaction mixture was stirred for 64 hours. TFA was evaporated in a rotary evaporator, then 200 ml of 95/5 CH 2 Cl 2 / MeOH was added, and then saturated NaHCO 3 solution was added until a pH of 10 was obtained. The organic phase was recovered and washed with water. After drying over MgSO 4 , the solvent was evaporated in a rotary evaporator to give 40 mg of the tetracyclic compound in the form of a brown powder, which was washed with ether.
    [177] 8-chloro-7H-pyrido [4,3,2-de] [1,7] phenanthroline-7-one (CRL 8396)
    [178]
    [179] Example 6
    [180] Methoxy-7H-pyrido [4,3,2-de] [1,10] phenanthroline-7-one (CRL 8400) and 4-methoxy-7H-pyrido [ -de] [l, 7] phenanthroline-7-one (CRL 8401)
    [181] 100 mg (0.39 mmol) of tricyclic I-8b or tricyclic II-8b in 0.7 ml of DMF and 0.27 ml (1.37 mmol) of dimethylformamide diethyl acetal were made to 120 ° C under nitrogen for 1 hour. After the solvent was evaporated with a vacuum pump, 0.6 g (11.7 mmol) of NH 4 Cl and 90 ml of absolute ethanol were added. The reaction mixture was refluxed for 30 minutes. After evaporating the ethanol with a rotary evaporator, 10 ml of water were added to the residue and extraction was carried out with CH 2 Cl 2 (10 ml three times). After drying the organic phase with MgSO 4, the solvent was evaporated with a rotary evaporator, to give written because filtration (95/5 CH 2 Cl 2 / MeOH ) on silica to give the compound CRL 8400 and CRL 8401 in the form of a brown powder.
    [182] 4-methoxy-7H-pyrido [4,3,2-de] [1,10] phenanthroline-7-one (CRL 8400)
    [183]
    [184] 4-methoxy-7H-pyrido [4,3,2-de] [1,7] phenanthroline-7-one- (CRL 8401)
    [185]
    [186] Example 7
    [187] 4,8-dimethoxy-7H-pyrido [4,3,2-de] [1,10] phenanthroline-7-one (CRL 8803) and 4,11-dimethoxy-7H- , 3,2-de] [1,7] phenanthroline-7-one (CRL 8440)
    [188] A solution of the compound I-9b or II-9b (100 mg, 0.35 mmol) and N, N-dimethylformamide diethyl acetal (0.24 ml, 1.23 mmol) in 1 ml DMF was made to 120 ° C for 90 minutes. The reaction mixture was concentrated under high vacuum to remove DMF, and the residue was diluted with 100 ml of anhydrous EtOH. After addition of 0.6 g of NH 4 Cl, the mixture was refluxed for 30 minutes. After concentration using a rotary evaporator, it was added to 30ml water, and the mixture was extracted with CHCl 3 (3 times 75ml). And it concentrated the organic phase was dried under MgSO 4. The resulting crude product was purified by flash chromatography on silica (95/5 CH 3 Cl 3 / MeOH) to give the compound in the form of a yellow powder.
    [189] 4,11-dimethoxy-7H-pyrido [4,3,2-de] [1,7] phenanthroline-7-one (CRL 8440)
    [190]
    [191] Example 8
    [192] 4-methoxy-8-dimethylamino-7H-pyrido [4,3,2-de] [1,10] phenanthroline-7-one (CRL 8804) 7H-pyrido [4,3,2-de] [1,7] phenanthroline
    [193] -7-one (CRL 8441)
    [194] A solution of the compound I-11b or II-11b (80 mg, 0.27 mmol) and N, N-dimethylformamide diethyl acetal (0.18 ml, 0.94 mmol) in 2 ml of DMF was made to 120 ° C for 3 hours. The reaction mixture was concentrated under high vacuum to remove DMF, and the residue was diluted with 90 ml of anhydrous EtOH. After addition of 0.4 g of NH 4 Cl, the mixture was refluxed for 30 minutes and then concentrated in a rotary evaporator. After addition of 30 ml of water, the solution was extracted with CH 2 Cl 2 (3 times 50 ml). And it concentrated the organic phase was dried under MgSO 4. The resulting crude product was purified by flash chromatography on silica (95/5 CH 2 Cl 2 / MeOH) to give the tetracyclic compound in the form of red-brown powder.
    [195] 4-methoxy-11-dimethylamino-7H-pyrido [4,3,2-de] [1,7] phenanthroline-7-one (CRL 8441)
    [196]
    [197] Example 9
    [198] 4,10-dimethoxy-7H-pyrido [4,3,2-de] [1,10] phenanthroline-7-one (CRL 8805) and 4,9-dimethoxy-7H- , 3,2-de] [1,7] phenanthroline-7-one (CRL 8479)
    [199] A solution of the compound I-12b or II-12b compound (100 mg, 0.35 mmol) in 1 ml of DMF and N, N-dimethylformamide diethyl acetal (0.24 ml, 1.23 mmol) was made to 120 ° C for 1 hour. The reaction mixture was concentrated under high vacuum to remove DMF, and the residue was diluted with 100 ml of anhydrous EtOH. After addition of 0.54 g of NH 4 Cl, the mixture was refluxed for 30 minutes. After concentration using a rotary evaporator, and extracted solution was added to 20ml of water with CHCl 3 (3 times 30ml). And it concentrated the organic phase was dried under MgSO 4. Purification by flash chromatography (CHCl 3) and the resulting crude product on silica in the form of a green powder was obtained a tetra-cyclic compound.
    [200] 4,9-dimethoxy-7H-pyrido [4,3,2-de] [1,7] phenanthroline-7-one (CRL 8479)
    [201]
    [202] Example 10
    [203] 7H-pyrido [4,3,2-de] [1,10] phenanthroline-7-one (CRL 8805) and 10-ethoxycarbonyl-7H-pyrido [ , 3,2-de] [1,7] phenanthroline-7-one (CRL 8482)
    [204] A solution of CH 2 Cl 2 15ml of compound I-13b or II-13b compound (30mg, 0.07mmol) and acetic acid (0.27ml, 3.5mmol) in trifluoroacetic was stirred for 64 hours. After concentration on a rotary evaporator, the reaction mixture was basified with 10 ml of saturated NaHCO 3 solution and extracted with CHCl 3 (30 ml twice). After drying the organic phase under MgSO 4 and concentrated in a rotary evaporator. The resulting residue was purified on silica to obtain a tetracyclic compound in the form of a yellow powder.
    [205] 7-Pyrido [4,3,2-de] [1,7] phenanthroline-7-one (CRL 8482)
    [206]
    [207] Example 11
    [208] 7H-pyrido [4,3,2-de] [1,10] phenanthroline-7-one (CRL 8809) and 9-hydroxy-7H-pyrido [ -de] [l, 7] phenanthroline-7-one (CRL 8483)
    [209] A solution of the compound I-14b or the compound II-14b (tricyclic 56) (50 mg, 0.135 mmol) in 30 ml of CH 2 Cl 2 and a solution of trifluoroacetic acid (0.54 ml, 7 mmol) was stirred for 48 hours. After concentration on a rotary evaporator, the reaction mixture was basified with 13 ml of saturated NaHCO 3 solution and extracted with CH 2 Cl 2 (7 times 30 ml). After drying the organic phase under MgSO 4 and concentrated in a rotary evaporator. The obtained residue was purified by flash chromatography (97/2 CH 2 Cl 2 / MeOH) to obtain a tetracyclic compound in the form of an orange powder.
    [210] Hydroxy-7H-pyrido [4,3,2-de] [1,7] phenanthroline-7-one (CRL 8483)
    [211]
    [212] Example 12
    [213] Methoxy-7H-pyrido [4,3,2-de] [1,10] phenanthroline-7-one (CRL 8810) and 9-methoxy-7H-pyrido [ -de] [l, 7] phenanthroline-7-one (CRL 8484)
    [214] A solution of the compound I-16b or II-16b (200 mg, 0.786 mmol) and N, N-dimethylformamide diethyl acetal (0.47 ml, 2.73 mmol) in 3.2 ml DMF was refluxed for 2 hours. The reaction mixture was concentrated under high vacuum to remove DMF, and the residue was diluted with 200 ml of anhydrous EtOH. After addition of 1.4 g (26.2 mmol) of NH 4 Cl, the solution was refluxed for 30 minutes. After concentrating on a rotary evaporator, 50 ml of water was added and the solution was extracted with CH 2 Cl 2 (5 times 40 ml). And it concentrated the organic phase was dried under MgSO 4. The resulting crude product was purified by flash chromatography on silica (99/1 CH 2 Cl 2 / MeOH) to give the tetracyclic compound in the form of a brown powder.
    [215] Methoxy-7H-pyrido [4,3,2-de] [1,7] phenanthroline-7-one (CRL 8484)
    [216]
    [217] Example 13
    [218] 7,10-dimethoxy-7H-pyrido [4,3,2-de] [1,10] phenanthroline-7-one (CRL 8811) and 9,11-dimethoxy-7H- , 3,2-de] [1,7] phenanthroline-7-one (CRL 8485)
    [219] A solution of the compound I-18b or II-18b (105 mg, 0.37 mmol) and N, N-dimethylformamide diethyl acetal (0.22 ml, 1.29 mmol) in 1.5 ml of DMF was refluxed for 1 hour 30 minutes. The reaction mixture was concentrated under high vacuum to remove DMF, and then the residue was diluted with 95 ml of anhydrous EtOH. 0.7 g (13.08 mmol) of NH 4 Cl was added and the solution was refluxed for 30 minutes. After concentrating on a rotary evaporator, 50 ml of water were added. The solution was extracted with CH 2 Cl 2 (5 times 40 ml). The organic phase was concentrated and dried under MgSO 4. The resulting crude product was purified by flash chromatography on silica (99/1 CH 2 Cl 2 / MeOH) to give the tetracyclic compound in the form of orange-yellow powder.
    [220] 9,11-dimethoxy-7H-pyrido [4,3,2-de] [1,7] phenanthroline-7-one (CRL 8485)
    [221]
    [222] Example 14
    [223] (CRL 8812) and 9-chloro-11-dimethylamino-7H-pyrido [4,3,2-de] [1,7] Pyrido [4,3,2-de] [1,7] phenanthroline
    [224] -7-one (CRL 8485)
    [225] A solution of the compound I-17b or the compound II-17b (110 mg, 0.375 mmol) and N, N-dimethylformamide diethyl acetal (0.23 ml, 1.31 mmol) in 1.1 ml of DMF was refluxed for 1 hour 30 minutes. The reaction mixture was concentrated under high vacuum to remove DMF, and then the residue was diluted with 95 ml of anhydrous EtOH. After addition of 0.7 g (13.08 mmol) of NH 4 Cl, the mixture was refluxed for 30 minutes and then concentrated in a rotary evaporator. After addition of 50 ml of water, the solution was extracted with CH 2 Cl 2 (5 times 40 ml). The organic phase was concentrated and dried under MgSO 4. The resulting crude product was purified by flash chromatography on silica (99/1 CH 2 Cl 2 / MeOH) to give the tetracyclic compound in the form of a purple-red powder.
    [226] 7-Pyrido [4,3,2-de] [1,7] phenanthroline-7-one (CRL 8486)
    [227] Example 15
    [228] 7H-pyrido [4,3,2-de] [1,10] phenanthroline-7-one dihydroiodide (CRL 8813) and 4-hydroxy-7H-pyrido [ 4,3,2-de] [1,7] phenanthroline-7-
    [229] Ondihydroiodide (CRL 8487)
    [230] Hydroiodic acid (57% in water: 10 ml, 44.6 mmol) was added to a suspension of CRL 8400 compound or CRL 8401 compound (50 mg, 0.19 mmol) in acetic acid (4 ml). The mixture was heated at 100 < 0 > C for 21 hours. After cooling and filtration, the dihydroiodide of the expected compound was isolated in the form of a purple powder.
    [231] 4-hydroxy-7H-pyrido [4,3,2-de] [1,7] phenanthroline-7-ondihydroisoiodide (CRL 8487)
    [232]
    [233] Example 16
    [234] 7H-pyrido [4,3,2-de] [1,10] phenanthroline-7-one (CRL 8806) and 4-chloro-7H-pyrido [ ] [1,7] phenanthroline-7-one (CRL 8480)
    [235] POCl3A solution of CRL 8813 compound or CRL 8487 compound (45 mg, 0.14 mol) in THF (3.5 ml) was refluxed for 2 hours. After evaporation in a rotary evaporator, the mixture was washed with 1N NaHCO3The solution was basified to pH 8 with 10 ml of 5% MeOH / CHCl33Extraction was carried out with the mixture (2 x 20 ml). The organic phases were washed with MgSO44≪ / RTI > and concentrated in a rotary evaporator. The resulting residue was purified by flash chromatography (99/1 CH2Cl2/ MeOH) < / RTI > to give The compound It was obtained in the form of a brown powder.
    [236] Chloro-7H-pyrido [4,3,2-de] [1,7] phenanthroline-7-one (CRL 8480)
    [237]
    [238] Example 17
    [239] 7H-pyrido [4,3,2-de] [1,10] phenanthroline-7-one (CRL 8807) and 4-dimethylamino-7H-pyrido [ -de] [l, 7] phenanthroline-7-one (CRL 8481)
    [240] A solution of CRL 8806 compound or CRL 8480 compound (14 mg, 0.052 mmol) in dimethylamine hydrochloride (24 mg, 0.29 mmol) and THF / H2O mixture (2 ml / 1 ml) was refluxed for 1 hour 30 minutes. After evaporation in a rotary evaporator, the mixture was charged with 15 ml of water. CHCl33(3x20ml), the organic phases were washed with MgSO44≪ / RTI > and concentrated in a rotary evaporator. The resulting residue was purified by flash chromatography (95/5 CHCl3/ MeOH) < / RTI > to give The compound Obtained in the form of a red powder.
    [241] 4-dimethylamino-7H-pyrido [4,3,2-de] [1,7] phenanthroline-7-one (CRL 8481)
    [242]
    [243] Example 18
    [244] 3-acetoxymethyl-7H-pyrido [4,3,2-de] [1,10] phenanthroline-7-one (CRL 8825) and 3- acetoxymethyl-7H-pyrido [ , 2-de] [1,7] phenanthroline-7-one (CRL 8824)
    [245] A solution of the compound I-1b and II-1b compound (0.11 g, 0.5 mmol) and dimethylformamide diethyl acetal (1.5 mmol) in DMF (3 ml) was heated at 120 < 0 > C for 1 hour in the presence of nitrogen. After cooling, the mixture was concentrated in vacuo to give the expected derivatives in solid form. The solid derivative (125 mg, 0.45 mmol) was charged with DMF and 13 mg (0.7 mmol) of Eschenmoser's salt was added. The mixture was heated at 115 < 0 > C for 30 minutes under a nitrogen atmosphere. After cooling, NH 4 Cl (10 mmol) and acetic acid (75 ml) were added to the mixture and brought to 115 ° C for 30 min. After cooling, the reaction mixture was basified with 10% KOH is poured on ice and extracted with CHCl 3. Dry the organic phase with MgSO 4 and concentrated in a rotary evaporator. The residue was purified by flash chromatography on silica.
    [246] 7H-pyrido [4,3,2-de] [1,10] phenanthroline-7-one (CRL 8815) and 3-acetal-7H-pyrido [ ] [1,7] phenanthroline-7-one (CRL 8814),
    [247] 7H-pyrido [4,3,2-de] [1,10] phenanthroline-7-one (CRL 8817) and 3-cyano-7H-pyrido [ -de] [1,7] phenanthroline-7-one (CRL 8816),
    [248] (CRL 8819) and 3-ethoxycarbonyl-7H-pyrido [4,3,2-de] [1,10] , 3,2-de] [1,7] phenanthroline-7-one (CRL 8818),
    [249] 7H-pyrido [4,3,2-de] [1,10] phenanthroline-7-one (CRL 8821) and 3-methoxymethyl-7H-pyrido [ , 2-de] [1,7] phenanthroline-7-one (CRL 8820),
    [250] 7H-pyrido [4,3,2-de] [1,10] phenanthroline-7-one (CRL 8823) and 3-fluoro-7H-pyrido [ -de] [1,7] phenanthroline-7-one (CRL 8822),
    [251] 3-acetoxymethyl-9H-pyrido [4,3,2-de] [1,10] phenanthroline-7-one (CRL 8825) 7H-pyrido [4,3,2-de] [1,7] phenanthroline-7-one (CRL 8824) is prepared according to the preparation method described above.
    [252] Example 19
    [253] Methyl-7H-pyrido [4,3,2-de] [1,10] phenanthroline-7-one (CRL 8827) ] [1,7] phenanthroline-7-one (CRL 8826)
    [254] A mixture of compound I-1b and II-b compound (80 mg, 0.4 mmol) was dissolved in acetic acid (10 ml) with ammonium chloride (64 mg, 12 mmol) and the solution was heated to 70 ° C with constant stirring. Acetaldehyde (88 mg, 2 mmol) in acetic acid (10 ml) was added dropwise. The mixture was heated to reflux in the presence of nitrogen for 45 minutes and then cooled. After addition of water, the solution was basified with NH 4 OH and extracted with dichloromethane. After drying with MgSO 4 and evaporated, the obtained residue was purified by flash chromatography on silica.
    [255] Benzyl-7H-pyrido [4,3,2-de] [1,10] phenanthroline-7-one (CRL 8829) ] [1,7] phenanthroline-7-one (CRL 8828),
    [256] (CRL 8831) and 2- (2'-chloroethyl) - 7H-pyrido [4,3,2-de] [1,10] phenanthroline- 7H-pyrido [4,3,2-de] [1,7] phenanthroline-7-one (CRL 8830)
    [257] (2'-methoxymethyl) -7H-pyrido [4,3,2-de] [1,10] phenanthroline- ) -7H-pyrido [4,3,2-de] [1,7] phenanthroline-7-one (CRL 8832) is prepared according to the preparation method described above.
    [258] The results of the in vitro and in vivo pharmacological tests shown below demonstrate the cytotoxic properties and the maximum tolerated dose (MTD) of the compounds of formula (I) and formula (Ia).
    [259] 1 - Cytotoxic activity of tumor cell lines in culture (MTT test)
    [260] The effects of compounds of formula (I) and (Ia) on tumor cells were evaluated using MTT colorimetric tests (T. Mosman, J. Immunol. Methods, 1983; 65: 55-63, J. Carmichael et al. Cancer Res., 1987; 47: 936-942).
    [261] The principle of the MTT test is that the yellow product MTT (3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide) is metabolized to the blue Lt; RTI ID = 0.0 > of formazan, < / RTI > The amount of formaldehyde thus obtained is directly proportional to the amount of living cells present in the culture wells or wells. The amount of formalin is measured by spectrophotometry.
    [262] The cell lines are monolayered at 37 占 폚 in lided culture dishes containing 25 mM HEPES MEM (minimal essential medium) basal medium. This medium is a well suitable for growing a wide range of diploid or primary mammalian cells. This medium is then supplemented with nutrients according to the following:
    [263] - 5% FCS (Foetal Calf Serum: fetal calf serum) supplemented at 56 ° C for 1 hour,
    [264] - L-Glutamine 0.6 mg / ml,
    [265] - penicillin 200 IU / ml,
    [266] - streptomycin 200 [mu] g / ml,
    [267] - Gentamicin 0.1 mg / ml.
    [268] The 12 human cancer cell lines used were purchased from the American Type Culture Collection (ATCC Rockville, Md., USA). These 12 cell lines are as follows:
    [269] - Two Glioblass Thomas in U-373MG (ATCC code: HTB-17) and U-87MG (ATCC code: HTB-14)
    [270] - astrocytoma, SW1088 (ATCC code: HTB-12),
    [271] - Two non-small-cell lung cancers, A549 (ATCC code: CCL-185) and A-427 (ATCC code: HTB-53)
    [272] - Two colorectal cancers, HCT-15 (ATCC code: CCL-225) and LoVo (ATCC code: CCL-229)
    [273] - Two breast cancers, T-47D (ATCC Code: HTB-133) and MCF7 (ATCC Code: HTB-22)
    [274] - Two bladder tumors, J82 (ATCC code: HTB-1) and T24 (ATCC code: HPB-4)
    [275] - PC-3, a prostate cancer (ATCC code: CRL-1435).
    [276] Experimental: 100 μl of the cell suspension containing 20,000 to 50,000 cells / ml of the medium (depending on the cell type used) was inoculated in a flat bottomed 96-well multi-well plate and incubated with 5% CO 2 and 70% Lt; RTI ID = 0.0 > 37 C. < / RTI > After incubation for 24 h, the medium was replaced with 100 ul of fresh medium containing various test compounds in which the concentration of the solvent (control conditions) used was 10 -5 M to 10 -10 M in order to dissolve the test product do. After 72 hours of incubation under these conditions, the medium is replaced with 100 μl of the yellow solution of dissolved MTT in RPMI 1640 at a rate of 1 mg / ml. The microplate is cultivated at 37 ° C for 3 hours and then centrifuged at 400 g for 10 minutes. After removal of the yellow solution of MTT, the blue formalin crystals produced at the cellular level are dissolved in 100 μl of DMSO. The microplate is then shaken for 5 minutes. The intensity of the resultant blue color and the intensity of the conversion of the yellow MTT product to the blue color form azane by living cells still alive at the end of the experiment are respectively 570 nm and 570 nm, Determined by spectrophotometric method using DYNATECH IMMUNOASSAY SYSTEM machine at 630nm. The software installed in the spectrophotometer calculates the standard error (SEM) of the mean optical density value or the standard deviation (Std. Dev.) And the mean value.
    [277] The inhibitory activity of the compounds of formula (I) and of formula (Ia) on cell growth of different tumor cell lines was evaluated relative to the activity of the natural product. The values of the concentrations forming the inhibitory concentrations (IC 50 ) obtained for each compound are shown in Table 1 below.
    [278] All of the compounds studied include 12 human tumor cell lines (U-87MG, U-373MG, SW 1088, T24, J82, HCT-15, LoVo, MCF7, T-47D, A549, A- the show significant inhibitory activity with respect to cell proliferation, and thus in the test tumor cell line with the compound shows a significant inhibition activity at IC 50 of 10 -5 M~10 -9 M.
    [279] 2 - Determination of maximum tolerated dose (MTD)
    [280] Assessment of the maximum tolerated dose was performed on B6D2F1 / JiCo mice 4-6 weeks old. Compounds were administered intraperitoneally with increasing doses ranging from 2.5 to 160 mg / kg. The value of MTD (expressed in mg / kg) was determined by observing the survival rate of the test animals over a period of 14 days after single administration of the product under consideration. Changes in animal weights are also monitored over this period. If the MTD value is greater than 160 mg / kg, the MTD value is classified as a default value of 160 mg / kg.
    [281] The evaluation results of the maximum allowable dose (MTD) are shown in Table 2 below.
    [282] Maximum acceptable dose CRL compoundsMTD (mg / kg) CRL 8388 (Example 4)10 CRL 8293 (Example 1)10 CRL 8294 (Example 1)10 CRL 8363 (Example 2)10 CRL 8364 (Example 2)5 CRL 8367 (Example 3)10 CRL 8396 (Example 5)20 CRL 8400 (Example 6)> 160 CRL 8401 (Example 6)> 160 CRL 8440 (Example 7)20 CRL 8441 (Example 8)> 160
    [283] The products of these families may exhibit direct cytotoxicity or may lack such direct cytotoxicity, but in the case of direct cytotoxicity insufficiency, considerably higher doses are used to achieve higher tissue concentrations in vivo.
    [284] 3- In vivo antitumor activity
    [285] The tests were run with the following models:
    [286] - Hormone - Infertile mouse breast carcinoma MXT (HI-MXT),
    [287] - Hormone-sensitive mouse breast adenocarcinoma MXT (HS-MXT),
    [288] - Lymphoma L1210.
    [289] A model of mouse breast adenocarcinoma MXT of Watson C. et al. (Cancer Res., 1997; 37: 3344-3348) transplanted into 4-6 week old B6D2F1 / Jico mice is derived from the ductal duct. Initially, mutated hormone-sensitive tumors (HS-MXT models) are generated in the direction of unmutated hormone-responsive tumors (HI-MXT model). It has been demonstrated that drugs with antitumor activity prolong the survival time of animals with HI-MXT tumors and HS-MXT tumors clinically. This is the case, for example, of cyclophosphamide, etoposide or adriamycin.
    [290] The model of lymphoma L 1210 is a model of L 1210 leukemia cells derived from mouse transplanted mice. They grow rapidly into subcutaneous solid tumors in all cases (L 1210 s.c.).
    [291] When the MTD value of the product is determined, its in vivo antitumor activity is determined by comparing MTD / 2, MTD / 4 and MTD / 2 for the model of breast adenocarcinoma of the HS-MXT and mouse breast tumor species HI- And MTD / 8 dose.
    [292] In all of the examples shown below, the controlled condition is that 0.2 ml of physiological saline containing the solvent used to dissolve the various compounds of formula (Ia) and the formula (I) used, By a batch consisting of nine or fifteen mice dosed three times per week (Monday, Wednesday and Friday).
    [293] During such a test, tumor growth or survival rate of mice was determined:
    [294] I) - Tumor growth was assessed by measuring the area of transplanted HS-MXT, HI-MXT or L 1210 tumors twice a week (Monday and Friday). This area is calculated by multiplying the values of the two largest vertical axes of the tumor. The values of these axes are calculated using a sliding caliper.
    [295] Ii) The survival rate of mice is calculated morphologically or as a T / C ratio as follows:
    [296]
    [297] These ratios represent the median survival time of the intermediate mice versus the median of placement of the control mice versus the median survival time of the mice. Thus, a significant (P < 0.05) increase in survival of animals is induced when the T / C index exceeds 130%. On the other hand, if the T / C value is less than 70%, the toxic effect is obtained.
    [298] 3.1.-Mouse Breast Carcinoma (HI-MXT)
    [299] The effects of CRL 8293 and CRL 8294 on the growth of HI-MXT tumors will be shown by way of example below. Under the given experimental conditions, each batch of mice transplanted with HI-MXT tumors consists of 15 mice.
    [300] Processing 1
    [301] CRT 8293 product is administered intraperitoneally. The first injection of the product is performed at a dose of 5 mg / kg on day 7 (D7) after transplantation for three consecutive weeks with three injections (Monday, Wednesday and Friday).
    [302] Treatment 2
    [303] CRL 8294 product is administered intraperitoneally. The first injection of the product is performed at a dose of 5 mg / kg on day 7 (D7) after transplantation for three consecutive weeks with three injections (Monday, Wednesday and Friday).
    [304] The reduction (-) or increase (+) of the area of HI-MXT tumors in treatment 1 and treatment 2 compared to the control state on day 21 after tumor implant, ie, after 6 doses of CRL 8293 product or CRL 8294 product Are shown in percentages in Table 3 below. 100% of the control animals are still alive 21 days after transplantation.
    [305] processTumor area (expressed in%) 1 (CRL 8293)-33 2 (CRL 8294)-36
    [306] These results indicate that both CRL 8293 and CRL 8294 products significantly reduce the growth of HI-MTX tumors. These results show that the products of formula I and formula Ia exhibit antineoplastic activity in vivo and in this model.
    [307] Mouse Breast Adenocarcinoma (HS-MXT)
    [308] The effect of the two products of CRL 8293 and CRL 8294 on the growth of HS-MXT tumors will be shown by way of example below. Each batch of mice transplanted with HS-MXT tumors according to the given experimental conditions consists of 9 mice.
    [309] Treatment 10
    [310] CRL 8293 product is administered intraperitoneally. The first injection of the product is performed at a dose of 3 mg / week (Monday, Wednesday and Friday) for 3 consecutive weeks at a dose of 5 mg / kg on day 7 (D7) after transplantation.
    [311] Processing 20
    [312] The CRL 8294 product is administered alone as an intraperitoneal route. The first injection of the product is performed at a dose of 3 mg / week (Monday, Wednesday and Friday) for 3 consecutive weeks at a dose of 5 mg / kg on day 7 (D7) after transplantation.
    [313] (-) or increase in the area of HS-MXT tumors induced by treatments 10 and 20 compared to the control status after 9 doses given in the experimental protocol of the two products of CRL 8293 and CRL 8294 on day 31 after tumor transplantation (+) Is expressed as a percentage in the following Table 4. 100% of the control animals are still alive on the 31st day after transplantation.
    [314] processTumor area (expressed in%) 10 (CRL 8293)-45 20 (CRL 8294)-64
    [315] These results indicate that the two products of CRL 8293 and CRL 8294 induce a significant reduction in the growth of HS-MXT tumors. These results show that, as in the HI-MXT model, the products of formula I and formula Ia exhibit considerably advantageous antitumor activity in the HS-MXT model.
    [316] 3.3.-Lymphoma L 1210
    [317] The effect of CRL 8294 on survival time of the mice will be shown below by way of example (Table 5). Each batch of mice transplanted with lymphoma L 1210 according to the given experimental conditions consists of 9 mice.
    [318] Processing 100
    [319] The CRL 8294 product is administered intraperitoneally alone. The first infusion of the product is performed at a dose of 1.25 mg / kg on day 7 (D7) after transplantation and three infusions per week (Monday, Wednesday and Friday) for three consecutive weeks.
    [320] processT / C (expressed in%) 100 (CRL 8294)136
    [321] The CRL 8294 compound of formula (I) exhibits antitumor activity in a model of subcutaneous lymphoma L 1210. This activity is characterized by a significant prolongation of the mean survival time of the intermediate mice in the batch of treated mice compared to the mean survival time of the intermediate mice of the batches of control mice.
    [322] 4-Allowable / cytotoxic activity ratio
    [323] The MTD / IC 50 ratio calculated by taking the ratio of the mean IC 50 value (expressed in nM) (calculated from the individual cytotoxic activity obtained in each of the 12 tumor states studied) to the IC 50 value The results are shown in Table 6 below. The MTD / IC 50 is expressed as a dimensionless number.
    [324] CRL compoundsIC 50 (nM)MTD / IC 50 MTD / IC 50 * CRL 8388 (Example 4)62000.0016One CRL 8293 (Example 1)12500.0085 CRL 8294 (Example 1)14500.0074.4 CRL 8363 (Example 2)5000.0212.5 CRL 8364 (Example 2)2700.01912 CRL 8367 (Example 3)16500.0063.8 CRL 8396 (Example 5)6000.03320.6 CRL 8400 (Example 6)3800.42262 CRL 8401 (Example 6)5331870 CRL 8440 (Example 7)100.421240 CRL 8441 (Example 8)5000319.8
    [325] *: The MTD / IC 50 ratio of the various compounds was calculated as the ratio of CRL 8388 to 1 for reference.
    [326] Compounds of formula (I) and formula (Ia) exhibit significant antitumor activity both in vitro and in vivo under the experimental conditions described above. They inhibit the growth of tumor cells in vitro, as indicated by the results of MTT colorimetric tests. They significantly inhibited the in vivo growth of HI-MXT and HS-MXT tumors and compared the mean survival time of intermediate mice in the placement of control mice with the mean survival Significantly increases time.
    [327] Because of their cytotoxic nature, the compounds of the general formula (I) and the general formula (Ia) are suitable as active ingredients of the medicaments necessary for the treatment of carcinomas and their metastases, either as described or in the form of acceptable pharmaceutical salts or solvates Can be used.
    [328] Compounds of general formula (I) and general formula (Ia) are generally administered in the necessary dosage units per square meter of body surface area or kg of weight. Preferably, the dosage unit is formulated as a pharmaceutical composition in which the active ingredient is mixed with one (or more) pharmaceutical excipient (s).
    [329] The compounds of the general formula (I) and the general formula (Ia) are administered at a dose of 0.05 to 350 mg / body surface area m2, preferably in the range of 0.5 to 300 mg / body surface area for a therapeutic treatment in the acute phase as a function of the number of treatment cycles for each treatment. At a dose of 50 mg / m 2 / day, depending on the cancer pathology of the patient in need of treatment. For the maintenance treatment, the compounds of the general formula (I) and the general formula (Ia) are administered at a dose of 0.05 to 25 mg / m 2 / day, preferably 0.1 to 1.5 mg / m 2 / day It will be advantageous to use it as a dose. They can be used in combination with antitumor drugs used in protocols for powerful combination chemotherapy.
    [330] In the pharmaceutical compositions of this invention for oral or intravenous administration, the active ingredient may be administered in the form of a unit dose, as a mixture with conventional pharmaceutical carriers suitable for human therapy. Suitable unit dosage forms include those that are administered orally, such as optionally tablets, or gelatine capsules, implantable dosage forms, and intravenous dosage forms.
    [331] For parenteral administration (intravenous infusion at a constant flow rate), a sterile aqueous suspension, a sterile isotonic saline solution, or a pharmaceutically acceptable diluent and / or solubilizer, such as propylene glycol, polyethylene glycol or beta -cyclodextrin, A sterile injectable solution is used.
    [332] Thus, in order to prepare an intravenous infusion solution for infusion for 1 to 24 hours, the following cosolvents may be used: alcohols such as ethanol; Or glycols such as polyethylene glycol or propylene glycol, and hydrophilic surfactants such as Tween 80.
    [333] When a solid composition in the form of tablets is prepared, a wetting agent such as sodium lauryl sulfate may be added to the active ingredients that are either micronized or not micronized, and the total combination may be, for example, silica, gelatin, starch, lactose, Magnesium stearate, talc, gum arabic, and the like. The tablets may be coated with sucrose, various polymers, or other suitable materials, and optionally the tablets may be processed such that the activity is prolonged or delayed so that a predetermined amount of the active ingredients is continuously released.
    [334] The preparation of gelatin capsules is obtained by mixing the active ingredient with a diluent such as glycol or glycerol ester and incorporating the resulting mixture into a flexible or rigid gelatin capsule.
    [335] The active ingredient may also be formulated in the form of microcapsules or microspheres, optionally comprising one or more scaffolds or additives.
    [336] The active ingredient may also be provided in the form of a complex with a cyclodextrin, such as, for example, -, - or -Cyclodextrin, 2-hydroxypropyl-beta-cyclodextrin or methyl-beta-cyclodextrin.
    [337] Compounds of general formula (I) and general formula (Ia) will be used for the treatment of most solid tumors due to their potent cytotoxic activity and are particularly useful for the treatment of brain tumors, lung cancer, ovarian tumors and breast tumors, endometrial cancer, colorectal cancer, And testicular tumors.
    权利要求:
    Claims (12)
    [1" claim-type="Currently amended] Compounds of the general formula &lt; RTI ID = 0.0 &gt; and their &lt; / RTI &gt; pharmaceutically acceptable acid addition salts:

    From here:
    R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, hydroxyl, -CHO, -OR 8 , -COOH, -CN, -CO 2 R 8 , -CONHR 8 , -CONR 8 R 9 , -NH 2 , -NHR 8 , -N (R 8 ) 2 , -NH-CH 2 -CH 2 -N (CH 3 ) 2 , -NH-CH 2 -CH 2 -Cl , -NHCOR 8 , morpholino, nitro, SO 3 H, &Lt; / RTI &gt;
    Wherein R 8 and R 9 are selected from C 1 -C 6 alkyl groups and phenyl (C 1 -C 4 ) alkyl groups, Ar is a C 6 -C 14 aryl group,
    R 6 is selected from hydrogen, halogen, C 1 -C 6 alkyl, or R 10 is selected from halogen or -OH, (C 1 -C 6 ) alkoxy or -O-CO- (C 1 -C 6 ) (CH 2 ) n R 10 group, -CN, -CO 2 Et, or -COR 11 group wherein R 11 is selected from C 1 -C 6 alkyl group and phenyl (C 1 -C 4 ) alkyl group, , and R 12 and R 13 is hydrogen or C 1 ~C 6 alkyl, phenyl (C 1 ~C 4) alkyl or R 14 is halogen, (C 1 ~C 6) alkoxy and -N (CH 3) from the second group N is selected from -NR 12 R 13 groups independently selected from the group - (CH 2 ) n R 14 wherein n is 1 to 6,
    R 7 is hydrogen, (C 1 ~C 6) alkyl, phenyl (C 1 ~C 4) alkyl, R 15 and R 16 is hydrogen, C 1 ~C 6 alkyl, phenyl (C 1 ~C 4) alkyl-type -NR 15 R 16 are independently selected from each other from the groups group, and R 17 is selected from hydrogen, halogens or -OH or (C 1 ~C 6) alkoxy group and n is 1 to 6, the - (CH 2) n R 17 .
    [2" claim-type="Currently amended] The method according to claim 1,
    R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, hydroxyl, -CHO, -OR 8 , -COOH, -CN, -CO 2 R 8 , -CONHR 8 , -CONR 8 R 9 , -NH 2 , -NHR 8 , -N (R 8 ) 2 , -NH-CH 2 -CH 2 -N (CH 3 ) 2 , -NHCOR 8 , morpholino, 3 H, &Lt; / RTI &gt;
    R 8 and R 9 are selected from C 1 to C 6 alkyl groups and Ar is selected from C 6 to C 14 aryl groups.
    [3" claim-type="Currently amended] The method according to claim 1,
    R 1, R 2, R 3 , R 4 and R 5 is hydrogen, halogen, C 1 ~C 6 alkyl, hydroxyl, -OR 8, -NO 2, -NH 2, -NHR 8, -NH (R 8 ) 2 , -NH-CH 2 -CH 2 -N (CH 3 ) 2 , -NH-CH 2 -CH 2 -Cl, -NHCOR 8 wherein R 8 is selected from C 1 -C 6 alkyl groups ,
    R 6 is hydrogen, R 10 is selected from halogen, -O-CO-CH 3 group - (CH 2) n R 10 group, C 1 ~C 6 alkyl group, and R 12 and R 13 is hydrogen or C 1 ~ C 6 alkyl group, a benzyl group or R 14 is halogen or (C 1 ~C 6) alkoxy group -N (CH 3) 2 is selected from the group n is 1 to 6, the - (CH 2) n R 14 independently of one another from the group is selected from -NR 12 R 13 group is selected, the
    R 7 is hydrogen or C 1 -C 6 alkyl, benzyl, -NR 15 R 16 group wherein R 15 and R 16 are selected from hydrogen, C 1 -C 6 alkyl and benzyl, and R 17 is hydrogen, halogen or -OH Or a (C 1 -C 6 ) alkoxy group and n is selected from the groups of the type - (CH 2 ) n R 17 , wherein n is from 1 to 6, and the compounds of the formula Acceptable acid addition salts.
    [4" claim-type="Currently amended] The compound of claim 3 , wherein at least one of R 1 , R 2 , R 3 , R 4 and R 5 is a -OR 8 group.
    [5" claim-type="Currently amended] The method of claim 3,
    R 1 is hydrogen, halogen or a hydroxyl group, a methoxy group, a nitro group, -NH 2, -NHCH 3, -NH -CH 2 -CH 2 -N (CH 3) 2, -NH-CH 2 -CH 2 - is selected from Cl or -NHCOCH 3 group,
    R &lt; 2 &gt; is hydrogen,
    R 3 and R 5 are selected from hydrogen or a hydroxyl group or a methoxy group.
    [6" claim-type="Currently amended] The method of claim 3,
    11-methoxy-7H-pyrido [4,3,2-de] [1,7] phenanthroline-
    11-chloro-7H-pyrido [4,3,2-de] [1,7] phenanthroline-
    Methoxy-7H-pyrido [4,3,2-de] [1,7] phenanthroline-7-one,
    4, 11-dimethoxy-7H-pyrido [4,3,2-de] [1,7] phenanthroline-
    4,9-dimethoxy-7H-pyrido [4,3,2-de] [1,7] phenanthroline-
    Methoxy-7H-pyrido [4,3,2-de] [1,7] phenanthroline-7-one,
    9,11-dimethoxy-7H-pyrido [4,3,2-de] [1,7] phenanthroline-
    3-acetoxymethyl-7H-pyrido [4,3,2-de] [1,7] phenanthroline-
    3-acetoxymethyl-9-methoxy-7H-pyrido [4,3,2-de] [1,7] phenanthroline-
    The compound of formula (I) and its pharmacologically active compound are characterized in that they are 2- (2-chloroethyl) -7H-pyrido [4,3,2-de] [1,7] phenanthroline- Acceptable Acid Additives.
    [7" claim-type="Currently amended] The method of claim 3,
    8-methoxy-7H-pyrido [4,3,2-de] [1,10] phenanthroline-
    8-chloro-7H-pyrido [4,3,2-de] [1,10] phenanthroline-
    Methoxy-7H-pyrido [4,3,2-de] [1,10] phenanthroline-7-one,
    4,8-dimethoxy-7H-pyrido [4,3,2-de] [1,10] phenanthroline-
    4,10-dimethoxy-7H-pyrido [4,3,2-de] [1,10] phenanthroline-
    Methoxy-7H-pyrido [4,3,2-de] [1,10] phenanthroline-7-one,
    8,10-dimethoxy-7H-pyrido [4,3,2-de] [1,10] phenanthroline-
    3-acetoxymethyl-7H-pyrido [4,3,2-de] [1,10] phenanthroline-
    3-acetoxymethyl-9-methoxy-7H-pyrido [4,3,2-de] [1,10] phenanthroline-
    The compound of formula (Ia), which is 2- (2-chloroethyl) -7H-pyrido [4,3,2-de] [1,10] phenanthroline- Acceptable Acid Additives.
    [8" claim-type="Currently amended] A pharmaceutical composition comprising an effective amount of a compound selected from the compounds according to any one of claims 1 to 7 for the treatment of cancer cell tumors and their metastases by cytotoxic properties.
    [9" claim-type="Currently amended] Use of a compound according to any one of claims 1 to 7 in the manufacture of an anti-cancer drug.
    [10" claim-type="Currently amended] A process for preparing a compound according to claim 1, comprising the steps of:
    a) a quinolinedione of the general formula:

    The azadiene of the general formula is reacted according to the heterodiels-alder reaction,

    (Where, X = CH 3)
    Obtaining a mixture of compounds of the general formula:

    b) optionally isolating compounds of general formula II and general formula IIa;
    c 1 ) Next, in order to obtain enamine of the following formula, the compound of formula II and / or formula IIa is reacted with dimethylformamide dimethylacetal,

    Functionalizing the enamine to introduce the R &lt; 6 &gt; and / or R &lt; 7 &gt; substituent and cyclizing to obtain a compound of formula I and /
    or
    c 2 ) simultaneously functionalizing and cyclizing to obtain a compound of formula I and / or of formula la;
    d) optionally isolating the compounds of formula I and formula Ia.
    [11" claim-type="Currently amended] A process for the preparation of a compound of general formula I or a general formula Ia according to claim 1, wherein R 6 and R 7 are hydrogen atoms, characterized in that it consists of the following steps:
    a) a compound of the general formula &lt; RTI ID = 0.0 &gt;

    The following general formula azadiene is reacted according to the heterodis-Alder reaction,

    (Where, X = CH 2 -CH 2 -NHBoc )
    Obtaining a mixture of compounds of the general formula:

    b) optionally separating compounds of general formula II and general formula IIa;
    c) cyclizing the compound of formula II and / or formula IIa in order to obtain a compound of formula I and / or of formula la;
    d) optionally isolating the compound of formula I or formula Ia.
    [12" claim-type="Currently amended] A method of treating a patient with cancer, comprising administering to the patient an effective amount of a compound according to claim 1.
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1999-08-13|Priority to FR9910493A
    1999-08-13|Priority to FR99/10493
    2000-08-11|Application filed by 파.세 라퐁, 라보라뜨와르 엘르 라퐁
    2000-08-11|Priority to PCT/FR2000/002313
    2002-07-10|Publication of KR20020056883A
    优先权:
    申请号 | 申请日 | 专利标题
    FR9910493A|FR2797446B1|1999-08-13|1999-08-13|Phenanthroline-7-ones derivatives and their therapeutic applications|
    FR99/10493|1999-08-13|
    PCT/FR2000/002313|WO2001012632A2|1999-08-13|2000-08-11|Phenanthroline-7-one derivatives and their therapeutic uses|
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