EP1161432A1 - Pharmazeutische zusammensetzung enthaltend polyaromatische verbindungen - Google Patents

Pharmazeutische zusammensetzung enthaltend polyaromatische verbindungen

Info

Publication number
EP1161432A1
EP1161432A1 EP00912716A EP00912716A EP1161432A1 EP 1161432 A1 EP1161432 A1 EP 1161432A1 EP 00912716 A EP00912716 A EP 00912716A EP 00912716 A EP00912716 A EP 00912716A EP 1161432 A1 EP1161432 A1 EP 1161432A1
Authority
EP
European Patent Office
Prior art keywords
compounds
chosen
pyrido
formula
quinoline
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00912716A
Other languages
English (en)
French (fr)
Inventor
Evelyne Deflourne
Nathalie Les Nouvelles BONTEMPS-SUBIELOS
Francis Darro
Jean Bastide
Robert Kiss
Armand Frydman
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Cephalon France SAS
Original Assignee
Laboratoire L Lafon SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Laboratoire L Lafon SA filed Critical Laboratoire L Lafon SA
Publication of EP1161432A1 publication Critical patent/EP1161432A1/de
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/16—Peri-condensed systems

Definitions

  • the present invention relates to pharmaceutical compositions based on polyaromatic compounds useful in particular as anti-tumor drugs.
  • cytotoxic treatments used to reduce the size of cancerous tumors, contain the development of the tumor process or, in too few cases still, suppress the clumps of cancer cells and the risk of metastases, combine chemicals d recent introduction with others that have been used for several decades.
  • 5-fluorouracil 5- FU
  • irinotecan or topotecan the specific inhibitors of topoisomerase I
  • the therapeutic arsenal available to treat colorectal tumors will also be enriched with the availability of oxaliplatin, new "donors" in situ of 5-FU or selective inhibitors of thymidylate synthetase.
  • This coexistence is not limited to the treatment of colorectal cancers since, also, chemotherapy of breast, ovarian and lung cancers now largely calls upon the family of taxane derivatives (paclitaxel, docetaxel).
  • the need for more effective and better tolerated treatments, thus improving the survival and quality of life of patients is imperative since, always taking the example of colorectal tumors, it has been estimated (SL Parker, T. Tong, S Bolden et al., CA Cancer J.
  • ecteinascidin-743 is the subject of extensive pre-clinical work (E. Igbicka et al, NCI-EORTC symposium, 1998; Abst. 130 p.34), as well as clinical trials intended for define its therapeutic potential as an anticancer drug (A. Bo man et al, NCI-EORTC symposium, 1998; Abst. 452 p.1 18; MNillanova-Calero et al, NCI-EORTC symposium, 1998; Abst. 453 p.1 18 ; M .X. Hillebrand et al, NCI-EORTC symposium, 1998; Abst. 455 p.1 19; E.
  • meridine a natural alkaloid extracted from sea squirt Amphicarpa meridiana or from marine sponge Corticum sp.
  • Meridine was isolated by Schmitz et al. (J. Org. Chem. 1991; 56: 804-808) then described for its antiproliferative properties on a murine leukemia model (P388) and antifungals in patent US-A-5,182,287 (Gunawardana et al. Of January 23, 1993 ). Its antifungal properties have been described by McCarthy et al. (J. of Nat.
  • cystodamine a pentacyclic alkaloid isolated from Ascidian Cystodytes dellechiajei by Bontemps et al. (Tetrahedron lett, 1994; 35: 7023-7026) which has activity on human leukemia lymphoblasts.
  • the subject of the present invention is a pharmaceutical composition comprising an effective amount of a compound chosen from the compounds of formula:
  • R, R 3 , R., R- and R are chosen from hydrogen, halogens, hydroxy groups, -CHO, -OR, -COOH, -CN, -CO2R, -CONHR, -CONRR ',
  • R and R ′ being chosen from C 1 -C 6 alkyl groups and Ar being a C 6 -C 14 aryl group,
  • R2 is chosen from the nitro and -NHCOCF3 groups, and the addition salts of these compounds with pharmaceutically acceptable acids.
  • a more particular subject of the present invention is the compounds chosen from the compounds of formula I and of formula II in which: R], R3, R4, are chosen from hydrogen, halogens, hydroxy, -CHO, -OR,
  • R2 is chosen from the nitro and -NHCOCF3 groups, and the addition salts of these compounds with pharmaceutically acceptable acids.
  • the subject of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of a compound chosen from the compounds of formula I in which R] is chosen from hydrogen and methoxy groups, -N (CH 3 ) 2 and the compounds of formula II in which R ⁇ is chosen from hydrogen and methoxy groups, N (CH 3 ) : and -NHCOCH, and R2 is the group - NHCOCF3 and the addition salts of these compounds with pharmaceutically acceptable acids.
  • the subject of the invention is a pharmaceutical composition comprising an effective amount of a compound chosen from the compounds of formula I in which R 3 is a group -COOEt and the compounds of formula II in which R 3 is a group -COOEt and R 2 is chosen from the groups -NHCOCF 3 and -NO 2 and the addition salts of these compounds with pharmaceutically acceptable acids.
  • the subject of the invention is a pharmaceutical composition comprising an effective amount of a compound chosen from the compounds of formula I in which R 4 is a methoxy group and the compounds of formula II in which R 4 is a group methoxy and R 2 is chosen from the groups -MHCOCF 3 and -N0 2 and the addition salts of these compounds with pharmaceutically acceptable acids.
  • addition salts with pharmaceutically acceptable acids designate the salts which give the biological properties of the free bases, without having an undesirable effect.
  • These salts can be in particular those formed with mineral acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; acidic metal salts, such as disodium orthophosphate and monopotassium sulfate, and organic acids.
  • the compounds of formulas I and II are obtained according to the general reaction scheme described by Kitahara et al. (Chem Pharm. Bull 1994; 42: 1363-1364) and Kitahara et al. (Tetrahedron 1998; 54: 8421-8432).
  • the compounds of formula II can be prepared by a hetero Diels-Alder reaction between a quinoline-5,8 dione substituted in position 4 and a substituted aza-diene, followed by the dehydrogenation of the intermediate dihydrogenated compound.
  • the compounds of formula I are prepared from the compounds of formula II by cyclization:
  • R- 2 M C0CF 3
  • LiBr are added to 60 ml of dioxane and the mixture is brought to reflux for 30 min.
  • the crude product obtained is purified by flash chromatography on silica (CH 2 C1 2 then CH 2 Cl 2 / MeOH, 99: 1) to obtain 205 mg of a yellow powder of compound CRL 8456 (or its oxo tautomer in position 8).
  • the crude product is purified by flash chromatography on silica (CH2CI2 then CH2Cb / MeOH, 98: 2) to obtain the compound CRL 8453 in the form of a brown powder (53 mg).
  • CRL 8427 12-dimethylamino-benzo [b] pyrido [4,3,2-tfe] [l] phenanthroline-8-one (CRL 8427) 40 mg of CRL 8427 were obtained in the form of a red powder according to the process described in example 6.
  • the evaluation of the maximum tolerated dose was carried out in B6D2Fl / Jico mice aged 4 to 6 weeks.
  • the compounds were administered intraperitoneally to increasing doses ranging from 2.5 to 160 mg / kg.
  • the value of the DMT (expressed in mg / kg) is determined from the observation of the survival rate of the animals over a period of 14 days after a single administration of the product considered. The weight evolution of the animals is also monitored during this period.
  • the influence of the compounds of formulas I and II on the neoplastic cells was evaluated using the MTT colorimetric test.
  • the principle of the MTT test is based on the mitochondrial reduction by metabolically active living cells of the MTT product (3- (4,5-dimethylthiazol-2-yl) -2,5 diphenyl tetrazohum bromide) in a yellow product blue, formazan.
  • the quantity of formazan thus obtained is directly proportional to the quantity of living cells present in the well (s) of culture. This quantity of formazan is measured by spectrophotometry.
  • the cell lines are maintained in monolayer culture at 37 ° C. in closed-cap culture dishes containing MEM 25 MM HEPES base medium (Minimum Essential Medium). This medium, suitable for the growth of a range of varied diploid or primary mammalian cells, is then added: - with an amount of 5% of SVF (Fetal Calf Serum) decomplemented at 56 ° C for 1 hour,
  • the 12 human cancer cell lines 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,
  • 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)
  • LoVo (ATCC code: CCL-229) which are two colorectal cancers
  • 100 ⁇ l of a cell suspension containing 20,000 to 50,000 (depending on the cell type used) cells / ml of culture medium are seeded in 96-well multi-well plates with a flat bottom and are incubated at 37 ° C, in an atmosphere comprising 5% C ⁇ 2 and 70% - humidity. After 24 hours of incubation, the culture medium is replaced by 100 ⁇ l of medium-fresh containing either the different compounds to be tested at concentrations varying from 10 " to 10 " M or the solvent used for the dissolution. products to be tested (condition control).
  • the culture medium is replaced by 100 ⁇ l of a yellowish solution of MTT dissolved at a rate of 1 mg / ml in RPMI 1640.
  • the microplates are incubated for 3 hours at 37 ° C and then centrifuged for 10 minutes at 400 g.
  • the yellowish solution of MTT is eliminated and the blue formazan crystals formed at the cellular level are dissolved in 100 ⁇ l of DMSO.
  • the microplates are then stirred for 5 minutes.
  • the intensity of the blue coloration therefore resulting from the transformation of the yellow MTT product into blue formazan by the cells still living during the experiment is quantified by spectrophotometry using a device of the DYNATECH IMMUNOASSAY SYSTEM type at the lengths d wave of 570 nm and 630 nm corresponding respectively to the wavelengths of maximum absorbance of formazan and to the background noise.
  • Software integrated into the spectrophotometer calculates the average values of optical density as well as the values of standard deviation (Dev. Std.) And standard error on the mean (ESM).
  • ESM standard error on the mean
  • All of the compounds of formula I and of formula II have a significant inhibitory activity on the cell proliferation of the 12 human tumor lines: U-87MG, U-373MG, SW 1088. T24, J82, HCT-15, LoVo, MCF7, T-47D, A549, A-427 and PC-3 with an inhibitory concentration of 50
  • IC 50 which is between 10 and 10 " ⁇ M, depending on the compounds and the tumor lines tested.
  • concentrations framing the IC 50 obtained on the different cell lines are given in the table II:
  • Table III gives the mean IC50 results (in nM) (calculated from cytotoxic activity on the 12 tumor lines studied) and the DMT / IC50 ratios (these ratios are calculated by making the ratio of DMT and IC50s expressed in dimensionless numbers).
  • the compounds described have, on the models of tumor cell lines, IC 50 (n-M) lower or equivalent to those of the natural compounds la (meridine and cystodamine). Their maximum tolerated doses are close to those of meridine and cystodamine. When their IC50 is significantly lower than that of natural products, the tolerance / cytotoxic activity ratios of the compounds exemplified in the present invention then become significantly higher than that of meridine and cystodamine as indicated in Table III. These compounds can therefore be used as an anti-tumor drug, for their cytotoxic properties, at higher tissue concentrations than those induced by natural meridine and cystodamine. They are therefore characterized by better therapeutic maneuverability.
  • the compounds of formulas I and II as described or in the form of acceptable pharmaceutical salts or solvates can be used as active pharmaceutical ingredients.
  • the compounds of formulas I and II are generally administered in dosage units established either per m of body surface area, or per kg of weight.
  • Said dosage units are preferably formulated in pharmaceutical compositions in which the active principle is mixed with one (or more) pharmaceutical excipient (s).
  • the compounds of formula I and II above can be used according to the cancer pathology of the subject to be treated at doses of between 0.05 and 350 mg / m 2 of body surface, preferably at doses of 0.5 to 50 mg / m / day for a curative treatment in its acute phase depending on the number of treatment cycles of each treatment.
  • the compounds of formulas I and II will advantageously be used
  • the active ingredients can be administered in unit administration forms, in admixture with conventional pharmaceutical carriers suitable for human therapy.
  • suitable unit dosage forms include oral forms such as tablets, optionally breakable or capsules, implants and intravenous dosage forms.
  • sterile aqueous suspensions for parenteral administration (intravenous infusion at constant flow rate), sterile isotonic saline solutions or sterile injectable solutions are used which contain pharmacologically compatible dispersing agents and / or solubilizing agents, for example propylene glycol or polyethylene glycol.
  • a cosolvent can be used: an alcohol such as ethanol, a glycol such as polyethylene glycol or propylene glycol and a hydrophilic surfactant such as Tween® 80.
  • a wetting agent such as lauryl sulphate can be added to the active principle, micronized or not. of sodium and the whole is mixed with a pharmaceutical vehicle such as silica, gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like.
  • the tablets can be coated with sucrose, various polymers or other suitable materials or else they can be treated so that they have a prolonged or delayed activity and that they continuously release a predetermined quantity of active principle.
  • a preparation in capsules is obtained by mixing the active principle with a diluent such as a glycol or a glycerol ester and by incorporating the mixture obtained in soft or hard capsules.
  • the active principle can also be formulated in the form of microcapsules or microspheres, optionally with one or more carriers or additives.
  • the active principle can also be presented in the form of a complex with a cyclodextrin, for example ⁇ -, ⁇ - or ⁇ -cyclodextrin, 2-hydroxypropyl- ⁇ -cyclodextrin or methyl- ⁇ -cyclodextrin.
  • a cyclodextrin for example ⁇ -, ⁇ - or ⁇ -cyclodextrin, 2-hydroxypropyl- ⁇ -cyclodextrin or methyl- ⁇ -cyclodextrin.
  • the compounds of formulas I and II will be used in the treatment of most solid tumors due to their powerful cytotoxic activities, in particular for treating brain tumors, lung cancers, ovarian and breast tumors, colorectal cancers, prostate cancers and testicular tumors.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
EP00912716A 1999-03-18 2000-03-17 Pharmazeutische zusammensetzung enthaltend polyaromatische verbindungen Withdrawn EP1161432A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR9903390A FR2790954B1 (fr) 1999-03-18 1999-03-18 Composition pharmaceutique a base de composes polyaromatiques
FR9903390 1999-03-18
PCT/FR2000/000672 WO2000055160A1 (fr) 1999-03-18 2000-03-17 Composition pharmaceutique a base de composes polyaromatiques

Publications (1)

Publication Number Publication Date
EP1161432A1 true EP1161432A1 (de) 2001-12-12

Family

ID=9543359

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00912716A Withdrawn EP1161432A1 (de) 1999-03-18 2000-03-17 Pharmazeutische zusammensetzung enthaltend polyaromatische verbindungen

Country Status (18)

Country Link
US (1) US6583150B1 (de)
EP (1) EP1161432A1 (de)
JP (1) JP2002539212A (de)
KR (1) KR20020001778A (de)
CN (1) CN1344269A (de)
AU (1) AU778375B2 (de)
BR (1) BR0009113A (de)
CA (1) CA2361810A1 (de)
CZ (1) CZ20013348A3 (de)
FR (1) FR2790954B1 (de)
HU (1) HUP0200408A3 (de)
IL (1) IL145127A0 (de)
NO (1) NO20014450L (de)
NZ (1) NZ513853A (de)
PL (1) PL350899A1 (de)
SK (1) SK12282001A3 (de)
WO (1) WO2000055160A1 (de)
ZA (1) ZA200107074B (de)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2797443B1 (fr) * 1999-08-13 2003-10-31 Lafon Labor Procede de prepartion de quinoleine-5,8-diones
WO2017059401A2 (en) * 2015-10-01 2017-04-06 Duke University Androgen receptor ligands

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB695752A (en) 1950-06-15 1953-08-19 Borg Warner Improvements in or relating to rotary pumps and bushings for rotary pumps
US5182287A (en) * 1989-11-03 1993-01-26 Harbor Branch Oceanographic Bioactive heterocycle alkaloids and methods of use
ES2088822B1 (es) * 1994-02-24 1997-08-01 Univ Madrid Complutense Nuevos derivados antraquinonicos con actividad antitumoral y sus aplicaciones.
GB9708751D0 (en) * 1997-04-29 1997-06-25 Univ Madrid Complutense New cytotoxic analogues of marine natural products derivatives of the pyrido (2,3,4-K1) acridine ring systems
GB9810998D0 (en) 1998-05-21 1998-07-22 Univ Madrid Complutense Antitumour 1,5-diazaanthraquinones

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0055160A1 *

Also Published As

Publication number Publication date
CZ20013348A3 (cs) 2002-05-15
FR2790954B1 (fr) 2003-08-08
AU778375B2 (en) 2004-12-02
ZA200107074B (en) 2002-08-27
KR20020001778A (ko) 2002-01-09
FR2790954A1 (fr) 2000-09-22
CN1344269A (zh) 2002-04-10
JP2002539212A (ja) 2002-11-19
HUP0200408A2 (hu) 2002-07-29
BR0009113A (pt) 2001-12-18
NO20014450D0 (no) 2001-09-13
PL350899A1 (en) 2003-02-10
AU3437400A (en) 2000-10-04
SK12282001A3 (sk) 2002-08-06
HUP0200408A3 (en) 2003-03-28
NZ513853A (en) 2001-09-28
CA2361810A1 (fr) 2000-09-21
WO2000055160A1 (fr) 2000-09-21
US6583150B1 (en) 2003-06-24
NO20014450L (no) 2001-11-16
IL145127A0 (en) 2002-06-30

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