WO2002020527A1 - Composes solubles permettant d'inhiber la resistance pleiotrope et compositions pharmaceutiques associees - Google Patents

Composes solubles permettant d'inhiber la resistance pleiotrope et compositions pharmaceutiques associees Download PDF

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Publication number
WO2002020527A1
WO2002020527A1 PCT/HU2001/000090 HU0100090W WO0220527A1 WO 2002020527 A1 WO2002020527 A1 WO 2002020527A1 HU 0100090 W HU0100090 W HU 0100090W WO 0220527 A1 WO0220527 A1 WO 0220527A1
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Prior art keywords
compounds
bis
group
fmoc
boc
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PCT/HU2001/000090
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English (en)
Inventor
János SEPRÕDI
Balázs SARKADI
Tamás HEGEDÛS
György Kéri
László ÕRFI
Miklós IDEI
Ferenc HOLLÓSY
István TEPLÁN
Yoshio Okada
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Solvo Biotechnology Inc.
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Priority to AU2001286131A priority Critical patent/AU2001286131A1/en
Publication of WO2002020527A1 publication Critical patent/WO2002020527A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to novel compounds having good solubility in a polar medium, particularly in weakly acidic medium, owing to their tertiary amino groups; and by means of their cyclic groups they are particularly suitable for inhibiting resistance developed against certain therapeu- tic agents in a patient.
  • the compounds of the present, invention are potent inhibitors of the so-called ABC transporter proteins of prokaryotic and eukaryotic origin (i.e. transporter proteins comprising an ATB binding Casette, e.g. MDR1, MRP2) .
  • the invention further relates to pharmaceutical compositions comprising the compounds of the invention.
  • the approach according to the invention is favorably applicable for the enhancement of the absorption and the effectiveness of the pharmaceutical agent in therapeutic treatments using hydrophobic pharmaceutical agents -. e.g. chemotherapy against cancer and parasites and treatments using pharmaceuticals acting in the brain -, due to the particularly good solubility of the active agent of the invention.
  • Chemotherapy is inapplicable when a patient becomes resistant to the chemotherapeutic.
  • a special form of drug resistance is called *multidrug resistance", which means that a type of cells becomes resistant not only to the chemotherapeutic being administered, but to a wide range of structurally and functionally unrelated drugs simultaneously [Ford et al.: Pharmacological Revi ews, £2, 155, (1992)].
  • Multidrug resistance refers to the ability of celis under chemotherapy to develop resistance to a broad range of structurally and functionally unrelated drugs. More specifically, ⁇ multidrug resistance” also applies to the cross-resistance between drugs which is adversely affected by the compounds of the present invention.
  • the cause of multidrug resistance is the appearance of specific glycoproteins in the plasma membrane of the targeted cell, e.g., a tumor cell.
  • ABC proteins belonging to the ABC (ATP Binding Cassette) protein group -, by using the energy of adenozine triphosphate (ATP) , remove or do not let into the cell many of the lipophilic compounds, including lipophilic che otherapeutics, keeping their concentration below the effective level [Higgins: Annu . Rev. Cell . Biol . _8, 67 (1992) ] .
  • ABC proteins that are already proven to cause resistance include P-glycoprotein (MDRl; see B. Sarkadi et al . : Hungarian patent specification No. 215,132), multidrug resistance protein (MRP1, ABCCl) and the multispecific organic an- ion transporter (MRP2, cMOAT, ABCC2) .
  • N MDR protein and "ABC protein” denote glycoproteins, which are present in the cell membranes of a variety of cell types, and as a result of their function a number of different compounds are secreted from the cell.
  • Multidrug transporters naturally are expressed and function in a greater extent in tissues responsible for extruding toxic materials and waste-products cells.
  • MDRl is expressed on the apical (luminal) part of the cells, among others in the epithelium of the bowels, and in the epithelium of blood vessels supplying the brain and the testis, wherein its main task is to provide protection against fat-soluble toxic agents (e.g. vinca alkaloids, anthracyclines) .
  • fat-soluble toxic agents e.g. vinca alkaloids, anthracyclines
  • It is present in the adrenal cortex, wherein it takes part in the secretion of hydrophobic hormones [Gottesman et al . : J. Biol . Chem. 263, 12163 (1988); Higgins et al . : see above].
  • the proteins of the MRP family secrete mainly anionic compounds from the cells (e.g. glutathione conjugates), but they are also capable of removing hydrophobic compounds (e.g. vinblastin, eto- poside, doxorubicin) .
  • the MRP1-3 proteins interact with meto- threxate as well.
  • the MRP1 protein is present throughout the body. In addition to developing drug resistance it takes a prominent part in inflammatory processes by transporting LTC 4 .
  • MRP2 primarily secrets bile salts in the liver and e.g. antibiotics in the proximal tubule of the kidney. [Borst et al . : BBA Bi omembr. , 1461, 347 (1999); Bakos et al . : Mol . Pharma- col . , 57, 760 (2000) ] .
  • Tumors developing from tissues highly expressing multidrug transporters are resistant to chemotherapy from the beginning and they show so-called primary drug resistance", while in other tumors a ⁇ secondary drug resistance" may develop as a result of the therapy.
  • the aim of the invention is to inhibit the activity of a member of the MDR or MRP family, and to provide agents combatting chemical resistance to address the clinical problem of multidrug resistance.
  • Toward this end we have prepared a set of novel, apolar molecules without electrical charge, containing several tertiary amino groups and having good solubility in water, which are defined below.
  • the invention relates to chemical compounds, which reduce or overcome multidrug resistance in a mammal, e.g. human, and in microorganisms causing disease in a mammal.
  • the compounds of the present invention are apolar compounds having good solubility in aqueous solutions, said compounds being capable of competing with the substrates of transporters causing multidrug resistance thereby reducing or eliminating multidrug resistance.
  • tertiary nitrogen atoms play an important role in anti multidrug resistance molecules, and at the same time they enhance the solu- bility of the molecule in aqueous solutions.
  • the compounds of the present invention by means of their tertiary nitrogen atoms acting as week bases (they can be converted easily into their salts by mineral and organic acids) are extremely soluble in aqueous-organic solvent mixtures and they do not precipitate from such solutions even after addition of large quantity of water, despite their apolar character. This is very important because one of the most important requirements for intravenous administration is that the active agent administered into the blood should not precipitate but remain in solution.
  • the compounds of the present invention contain acid amide bonds but they are not of peptide linkage nature thus they are resistant to the known enzymes.
  • the compounds of the present invention effectively inhibit expulsion of hydrophobic therapeutic compounds from cells. They are effective at low concentrations, they are further characterized by good solubility, they are not toxic, and their effect is reversible (i.e. once they are eliminated, the function of the transporter recovers) . Side effects have not been observed. They are especially advantageous for overcoming resistance against anticancer drugs, without causing serious side-effect in other tissues, and without irreversibly disrupting the important natural physiological function of the transport protein itself.
  • the invention relates to compounds of general formula (I)
  • T represents a chemical bond; a piperidyl group optionally substituted with 1-8 substituents selected independently from C ⁇ -6 alkyl and C ⁇ - 6 alkoxy groups; or a pyrrolidyl group optionally substituted with 1-6 substituents selected independently from C ⁇ -6 alkyl and C ⁇ _ 6 alkoxy groups; and
  • X represents an acyl group derived from an amino acid protected on its functional group (s); their pharmaceutically acceptable salts and pharmaceutical compositions thereof.
  • the compounds of the present invention are capable for the inhibition of resistance developed against certain therapeutic agents in a patient.
  • MRP family of transport proteins structurally related to MDR proteins m.p. melting point
  • Trt triphenylmethyl Trt triphenylmethyl .
  • Preferred compounds of formula ( I are the compounds of formula ( IA)
  • each R independently represents a C ⁇ _ 6 alkyl or a Ci-g alkoxy, and n is an integer from 0 to 8;
  • X represents a group as defined above.
  • each R substituent represents a methyl group and n is an integer from 2 to 6.
  • Especially preferred compounds are those of formula (IB) :
  • X represents a group as defined above.
  • the ⁇ amino acid is understood to be an amino acid containing a functional group or at least a heteroatom in its side chain, for example a carboxyl, amino, hydroxyl, thio or guanidino functional group or a ring nitrogen atom, preferably a carboxyl or amino group.
  • amino acids include from the naturally occurring amino acids for example aspartic acid (Asp) , glutamic acid (Glu) , lysine (Lys) , ornithine (Orn) , tyrosine (Tyr) , cysteine (Cys) , arginine (Arg) , tryptophan (Trp) , and from the not naturally occurring amino acids for example 3,5- diaminobenzoic acid (DAB) and 3, 4-diaminobenzoic acid.
  • Asp aspartic acid
  • Glu glutamic acid
  • Glu lysine
  • Orn ornithine
  • Tyr tyrosine
  • cysteine Cys
  • Arg arginine
  • Trp tryptophan
  • Preferred are Asp, Glu, Trp, Lys and DAB.
  • the role of the ⁇ protecting group" in the compounds ac- cording to the invention is to ensure the apolarity of the molecule by connecting to the polar functional group of the amino acid and thus terminating the polar functional group, particularly the carboxyl or amino group by an apolar group.
  • ⁇ protecting group is understood to be for example a protecting group commonly used in the peptide chem- istry [Peptides 2000, Eds. Jean Martinez, Jean-Alain Fehrentz, EDK Paris, France, 2001] .
  • Suitable groups for protecting the carboxyl group of an amino acid include for example the ester-type groups commonly used in the peptide chemistry, such as OBzl, OcHex, OtBu or OMe.
  • Suitable groups for protecting the amino group of an amino acid include for example the urethane-type groups commonly used in the peptide chemistry, such as BOC, FMOC or Z.
  • Suitable groups for protecting the -SH functionality include for example trityl or benzyl.
  • Suitable groups for protecting the guanidino functionality include for example Tos or PMC.
  • Phenolic hydroxyl may be protected preferably by a benzyl group.
  • the protecting group is selected preferably from OBzl, OtBu, OMe BOC, FMOC or Z.
  • X represents BOC-Glu (OBzl) -, BOC-Asp (OBzl) -, FMOC-D/L-Asp(OtBu)-, Z-D/L-Asp (-) -OMe, Z-D/L-Lys (Z) -, FMOC- D/L-Lys (BOC)-, FMOC-D/L-Trp- or Z 2 -DAB- .
  • Especially preferred compounds of formula (I) are the fol- lowings :
  • any of the compounds of the invention can be combined with a pharmaceutically acceptable carrier and/or an adjuvant usually applicable in the preparation of parmaceutical compositions.
  • the various compounds of the invention can also be combined with another drug, e.g. a chemotherapeutic, antipara- sitic or antibiotic drug in order to broaden the spectrum of activity or to simplify the simultaneous administration.
  • the compounds of the present invention may act as synergists.
  • an ⁇ active agent" or a fl drug includes any compound that is intended for use in diagnosis, cure, mitigation, treatment or prevention of a disease.
  • the compounds of the invention are suitable for reducing the resistance-causing activity of a multidrug transporter protein or its analogues. Such an application involves administering to the mammal any of the compounds of formula (I) in a therapeutically effective amount, preferably in an amount of 0.1 to 100 mg/kg body weight.
  • the compounds of the invention may be used to facilitate administration of a drug through membranes, which protect a given type of cell from foreign substances and/or exclude various substances from a given type of cell.
  • the compounds of the invention can be used to aid transport of a drug through the blood-brain barrier, or through the blood- testis barrier, or to facilitate the absorption through the intestinal wall.
  • ⁇ barrier is meant the endothelial lining of cells that are selectively impenetrable or impermeable to hydrophobic therapeutic agents.
  • a *therapeutically effective amount refers to an amount of a compound of formula (I) that is effective at reducing the activity of the multidrug transporter protein; an amount that is effective at lowering resistance to a drug or to a group of drugs; or an amount that is effective for facilitating absorption of a drug through the blood-brain barrier.
  • the w therapeutically effective amount can be calibrated by the assays described below.
  • * facilitating is meant enhancing the overall amount of the drug that is absorbed, or the fraction of the drug that is absorbed.
  • the compounds of the present invention are compounds comprising several rings and tertiary amino moieties, in which the tertiary amine moieties facilitate the solubility in polar solvents, the cyclic carbon chains ensure the apolarity of the molecule, and these hydrophobic groups enhance their interac- tion with MDRl transporters.
  • compounds of formula (I) can be synthesized by reacting an amine corresponding to formula (I) but containing hydrogen atom instead of the above defined acyl group X, with a reagent capable of introducing an acyl group X, using meth- ods and reagents that are known and commonly used in the field of organic chemistry.
  • a suitable apolar solvent such as di eth- ylformamide or acetonitrile .
  • the solution is cooled to a temperature of -5 to +5 °C, preferably to 0 °C, and the pH value of the solution is adjusted to the natural range, e.g. between 6 and 8, preferably to 7 by adding for example triethyl amine or ethyl diisopropyl amine.
  • a known condensing agent preferably DCC is added and the reaction mixture is then stirred at room temperature for 12-24 hours (depending on the reactants) .
  • the raw compounds of the invention obtained by said con- densation reaction are then isolated from the reaction mixture by a known procedure such as filtration of the precipitate byproduct, washing the compounds of the invention dissolved in an organic solvent with dilute aqueous acid or base or saline solution, and evaporation of the solvent. Then, if desired, the final products are further purified in order to remove contaminants from the compounds according to the present invention.
  • the final purification can include one or a combina ⁇ tion of the following procedures: gel filtration, medium or high pressure liquid column chromatography or silica gel column chromatography.
  • the compounds obtained as final products are characterized by thin layer chromatography analysis and by their melting point.
  • acylation can be carried out by using an ac- tive ester that is capable of introducing the group X, by a method known to those skilled in the art.
  • 1-hydroxybenztriazole in case of acylation with an optically active amino acid, 1-hydroxybenztriazole can be used as additive in order to activate the reagent and to avoid racemization [W. Lonig et al: Chem . Ber . , 103, 2024 (1970)].
  • R f values were obtained by thin layer chromatography analysis on Kiesel gel sheets (CD Alufolien, Merck) using the following solvent mixtures (in the examples the solvent mixtures will be identified by numbers listed below) :
  • Two test systems were developed to specifically assess the ability of a compound (e.g. a compound according to the invention) to interact with the human multidrug transporters (e.g. MDRl, MRPl) .
  • the first system measures the ATPase activity of multidrug transporter proteins, while the second system measures the level of a fluorescent indicator extruded by the above-mentioned transporter proteins.
  • the ATPase activity of multidrug resistance proteins reflects the interaction and relative affinity of a test co - pound to a given transporter.
  • ATPase activity of a given MDR protein is stimulated by toxic agents and glutathione conjugates thereof, while said ATPase is insensitive to chemicals with which the transporter does not interact.
  • the ATPase activity of transporters is also stimulated by known che osensi- tizing agents, such as the multidrug resistance inhibiting agents (e.g. verapamil), presumably by competing with substrates of the multidrug transporter.
  • Spodoptera frugiperda (Sf9) cells were infected with a recombinant vector of bacul ovirus origin carrying the human multidrug resistance protein (MDRl, MRPl, MRP2 ) gene.
  • the the cDNA of the multidrug resistance protein to be examined was inserted into the vector by genetic engineering [Germann et al. Biochemistry, 29, 2295 (1998); and Sarkadi et al . (1992) supra] .
  • Cells infected with the recombinant virus express a large quantity of protein, the expressed protein folds into the normal tertiary structure and it is built into the cell membrane retaining its function.
  • the infected cells were cultured according to known procedures [Germann et al . (1990) supra; Sarkadi et al . (1992) supra] .
  • the virus-infected Sf9 cells were harvested, and their membranes isolated and stored according to known procedures.
  • the amount of ATP consumption measured in these membranes re- fleets the ATP-dependent transport function of the multidrug transporter.
  • ATPase activity of the isolated Sf9 cell membranes was estimated by measuring inorganic phosphate (Pi) liberation.
  • ATPase activity was carried out as follows: a membrane suspension containing about 10 ⁇ g membrane protein was incubated at 37 °C in 0.1 ml of a medium containing 50 mM Tris-Mes (pH 6.8), 2 mM EGTA, 2 mM (in case of MRPl-2 5 mM) DTT, 50 mM KCl and 50 mM Na-azide. The ATPase reaction was started by the addition of 5 mM (in case of MRPl-2 6 mM) MgATP. The reaction was stopped by the addition of 0.1 ml of 5% SDS solution, and the amount of Pi determined immediately.
  • a membrane suspension containing about 10 ⁇ g membrane protein was incubated at 37 °C in 0.1 ml of a medium containing 50 mM Tris-Mes (pH 6.8), 2 mM EGTA, 2 mM (in case of MRPl-2 5 mM) DTT, 50 mM
  • ATPase activity was estimated by the difference obtained in Pi levels by a sensitive colorimetric assay between zero minutes (reaction stopped immediately with SDS) and 20 minutes (in case of MRPl-2 60 minutes) incubation period. Isolated membranes of uninfected and ⁇ galactosidase infected Sf9 cells had no drug-stimulated ATPase activity.
  • Fluorescent assay for the activity of the compounds of the invention is based on the measurement of fluorescent dye uptake into the intact cells. Fluorescent dyes are often used to indicate intracellular calcium concentration or pH changes.
  • An effective technique for cellular dye loading is the application of acetoxy-methylester (AM) derivatives. These hydrophobic dye esters are non-fluorescent outside the cell, but they are cleaved by intracellular esterases into hydro- philic fluorescent free acids. This intracellular * trapping" of the negatively charged dye molecule, and the continuous inward gradient of the AM compounds results in the accumulation of large amounts of fluorescent indicator inside the cell.
  • AM acetoxy-methylester
  • the free dye is a substrate of the proteins of the MRP family, but in the concentration applied, and during the time of the measurement the outward gradient of the dye is not considerable.
  • Assaying the compounds of the invention in cell cultures HL60 cells were cultured in RPMI medium, while MDCK cells were cultured in D-MEM medium, using known procedures.
  • Cells expressing MDRl and MRPl proteins and cells expressing MRP2 protein were prepared according to known techniques, and their multidrug-resistance was demonstrated as described [Ambudkar et al.: Proc . Na tl . Acad. Sci . , USA, 89, 8472 (1992); Sarkadi et al. (1992) supra] .
  • the effect of the compounds according to the invention on the activity of the MDR proteins was examined by a fluorescent dye extrusion assay.
  • the HL60 cells expressing the human multidrug transporter actively extrude the AM derivatives of fluorescent dyes. [Homolya et al . : J. Bi ol . Chem . , 29, 21493 (1993); Hollo et al . : Blochem . Biophys . Acta, 1191, 384 (1994) ] . Verapamil and the compounds according to the invention inhibit this dye extrusion, most probably by competing with the dye on the transporter, resulting in the increase of the fluorescence in the cell.
  • HPM1 solution centrifugation, suspension
  • the cells were placed into a cuvette in a concentration of 2xl0 5 /ml and accumulation of the fluorescent dye was measured with rapid stirring in a Hitachi F-4000 fluorescent spectrophotometer, both in the presence and in the absence of verapamil and the com- pounds of the invention.
  • the excitation wavelength was 480 nm, and emission was measured at 515 nm.

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Abstract

La présente invention concerne des composés représentés par la formule générale (I) dans laquelle T représente une liaison chimique; un groupe pipéridyle éventuellement substitué par 1 à 8 substituants choisis indépendamment les uns des autres dans les groupes C1-16 alkyle et C1-16 alcoxy; ou un groupe pyrrolidyle éventuellement substitué par 1 à 6 substituants choisis indépendamment les uns des autres dans les groupes C1-16 alkyle et C1-16 alcoxy; et X représente un groupe acyle dérivé d'un acide aminé protégé sur son/ses groupe(s) fonctionnel(s). L'invention concerne également les sels pharmaceutiquement acceptables de ces composés ainsi que des compositions pharmaceutiques associées. Les composés décrits dans cette invention permettent d'inhiber la résistance développée contre certains agents thérapeutiques chez un patient.
PCT/HU2001/000090 2000-09-08 2001-09-07 Composes solubles permettant d'inhiber la resistance pleiotrope et compositions pharmaceutiques associees WO2002020527A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001286131A AU2001286131A1 (en) 2000-09-08 2001-09-07 Soluble compounds for the inhibition of multidrug resistance and pharmaceutical compositions thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HU0003554A HUP0003554A2 (hu) 2000-09-08 2000-09-08 Multidrogrezisztencia megszüntetésére alkalmas oldékony peptidek, ezeket tartalmazó gyógyászati készítmények és ezek alkalmazása
HUP0003554 2000-09-08

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8129197B2 (en) 2006-05-12 2012-03-06 SOLVO Biotechnológial ZRT. Cholesterol loaded insect cell membranes as test proteins

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995032974A1 (fr) * 1994-06-01 1995-12-07 Ciba-Geigy Ag Derives de carbazole utilises comme agents agissant contre la resistance multiple aux anticancereux
US5723459A (en) * 1991-05-09 1998-03-03 Vertex Pharmaceuticals Incorporated Biologically active acylated amino acid derivatives

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5723459A (en) * 1991-05-09 1998-03-03 Vertex Pharmaceuticals Incorporated Biologically active acylated amino acid derivatives
WO1995032974A1 (fr) * 1994-06-01 1995-12-07 Ciba-Geigy Ag Derives de carbazole utilises comme agents agissant contre la resistance multiple aux anticancereux

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8129197B2 (en) 2006-05-12 2012-03-06 SOLVO Biotechnológial ZRT. Cholesterol loaded insect cell membranes as test proteins

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HU0003554D0 (en) 2000-11-28
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